Dipeptide derivatives

ABSTRACT

This invention is directed to compounds of the formula  
                 
 
     and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis and/or frailty, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis and/or frailty when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of Formula I.

[0001] This invention relates to dipeptide compounds which are growthhormone secretagogues and are useful for the treatment and prevention ofosteoporosis and/or frailty.

BACKGROUND OF THE INVENTION

[0002] Growth hormone (GH), which is secreted from the pituitary gland,stimulates growth of all tissues of the body that are capable ofgrowing. In addition, growth hormone is known to have the followingbasic effects on the metabolic processes of the body:

[0003] 1. Increased rate of protein synthesis in substantially all cellsof the body;

[0004] 2. Decreased rate of carbohydrate utilization in cells of thebody; and

[0005] 3. Increased mobilization of free fatty acids and use of fattyacids for energy.

[0006] Deficiency in growth hormone results in a variety of medicaldisorders. In children, it causes dwarfism. In adults, the consequencesof acquired GH deficiency include profound reduction in lean body massand concomitant increase in total body fat, particularly in the truncalregion. Decreased skeletal and cardiac muscle mass and muscle strengthlead to a significant reduction in exercise capacity. Bone density isalso reduced. Administration of exogenous growth hormone has been shownto reverse many of the metabolic changes. Additional benefits of therapyhave included reduction in LDL cholesterol and improved psychologicalwell-being.

[0007] In cases where increased levels of growth hormone were desired,the problem was generally solved by providing exogenous growth hormoneor by administering an agent which stimulated growth hormone productionand/or release. In either case the peptidyl nature of the compoundnecessitated that it be administered by injection. Initially the sourceof growth hormone was the extraction of the pituitary glands ofcadavers. This resulted in an expensive product, and carried with it therisk that a disease associated with the source of the pituitary glandcould be transmitted to the recipient of the growth hormone (e.g.,Jacob-Creutzfeld disease). Recently, recombinant growth hormone hasbecome available which, while no longer carrying any risk of diseasetransmission, is still a very expensive product which must be given byinjection or nasal spray.

[0008] Most GH deficiencies are caused by defects in GH release, notprimary defects in pituitary synthesis of GH. Therefore, an alternativestrategy for normalizing serum GH levels is by stimulating its releasefrom somatotrophs. Increasing GH secretion can be achieved bystimulating or inhibiting various neurotransmitter systems in the brainand hypothalamus. As a result, the development of synthetic growthhormone-releasing agents to stimulate pituitary GH secretion are beingpursued, and may have several advantages over expensive and inconvenientGH replacement therapy. By acting along physiologic regulatory pathways,the most desirable agents would stimulate pulsatile GH secretion, andexcessive levels of GH that have been associated with the undesirableside effects of exogenous GH administration would be avoided by virtueof intact negative feedback loops.

[0009] Physiologic and pharmacologic stimulators of GH secretion, whichinclude arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon,vasopressin, and insulin induced hypoglycemia, as well as activitiessuch as sleep and exercise, indirectly cause growth hormone to bereleased from the pituitary by acting in some fashion on thehypothalamus perhaps either to decrease somatostatin secretion or toincrease the secretion of the known secretagogue growth hormonereleasing factor (GHRF) or an unknown endogenous growthhormone-releasing hormone or all of these.

[0010] Obesity is a major risk factor for diabetes, and a large fractionof NIDDM patients are obese. Both conditions are characterized byelevated circulating insulin levels and suppressed GH levels. GHtreatment of GH-deficient adults (Jorgensen, J. O. L., et al., Lancet1:1221 (1989)), obese women (Richelsen, B., et al., Am J Physiol,266:E211 (1994)) and elderly men (Rudman, D., et al, Horm Res 36 (Suppl1):73 (1991)) has been shown to produce increases in lean body, hepaticand muscle mass while decreasing fat mass. Thus, GH therapy for obesitywould seem attractive except for the diabetogenic effects of GH.

[0011] An alternative to exogenous GH administration is therapy thatstimulates endogenous GH secretion. It has been shown that a substantialpituitary reserve of GH is present in pituitary-intact GH-deficientpatients and the elderly so that decreased serum GH levels are due tohyposecretion.

[0012] Hyposecretion of GH in several clinical settings (obesity, aging,glucocorticoid suppression) is relatively resistant to stimulation byGHRH (Gertz, B. J., et al., J Clin Endocrinol Metab, 79:745 (1994);Arvat, E., et al., J Clin Endocrinol Metab, 79:1440 (1994); Maccario,M., et al., Metabolism, 44:134 (1995)). In contrast, administration of aGHRP or combined administration of GHRH and a GHRP in these patients canelicit a robust GH response (Aloi, J. A., et al., J Clin EndocrinolMetab, 79:943; (1994)). Single dose studies of GHRPs have demonstratedthe absence of an acute effect on circulating insulin or glucose levels.Insulin and glucose have generally not been monitored in chronic studiesexcept to document the absence of unfavorable changes (Jacks, T., etal., J Endocrinol. 143:399 (1993)).

[0013] Prior to the present invention, the use of GHRPs or GHRP mimeticsto improve glycemic control has not specifically been explored. Themethod of treating insulin resistance in a mammal comprising theadministration of a compound of Formula I of this invention is practicedpreferentially in patients who have a functional hypothalamic-pituitaryaxis capable of GH secretory responses to GHRPs and who have pancreaticbeta-cells capable of secreting insulin.

[0014] Other compounds have been developed which stimulate the releaseof endogenous growth hormone such as analogous peptidyl compoundsrelated to GRF or the peptides of U.S. Pat. No. 4,411,890. Thesepeptides, while considerably smaller than growth hormones, are stillsusceptible to various proteases. As with most peptides, their potentialfor oral bioavailability is low.

[0015] WO 94/13696 refers to certain spiropiperidines and homologueswhich promote release of growth hormone. Preferred compounds describedtherein are of the general structure shown below.

[0016] WO 94/11012 refers to certain dipeptides that promote release ofgrowth hormone. These dipeptides have the general structure

[0017] The compounds of WO 94/11012 and WO 94/13696 are reported to beuseful in the treatment of osteoporosis in combination with parathyroidhormone or a bisphosphonate.

[0018] PCT publication WO 97/09060 discloses the use of growth hormonereleasing hormone or a functional analog thereof in the treatment ofinsulin resistance in mammals.

SUMMARY OF THE INVENTION

[0019] This invention provides compounds of the formula:

[0020] or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug,

[0021] wherein

[0022] HET is a heterocyclic moiety selected from the group consistingof

[0023] d is 0, 1 or2;

[0024] e is 1 or2;

[0025] A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of

[0026] —NR²—C(O)—NR²—,

[0027] —NR²—S(O)₂—NR²—,

[0028] —O—C(O)—NR²—,

[0029] —NR²—C(O)—O—,

[0030] —C(O)—NR²—C(O)—,

[0031] —C(O)—NR²—C(R⁹R¹⁰)—,

[0032] —C(R⁹R¹⁰)—NR²—C(O)—,

[0033] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0034] —S(O)₂—C(R⁹R¹⁰l)—C(R⁹R¹⁰)—,

[0035] —C(R⁹R¹⁰)—O—C(O)—,

[0036] —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—,

[0037] —NR²—C(O)—C(R⁹R¹⁰)—,

[0038] —O—C(O)—C(R⁹R¹⁰)—,

[0039] —C(R⁹R¹⁰)—C(O)—NR²—,

[0040] —C(O)—NR²—C(O)—,

[0041] —C(R⁹R¹⁰)—C(O)—O—,

[0042] —C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0043] —C(O)—O—C(R⁹R¹⁰)—,

[0044] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0045] —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0046] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—,

[0047] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—,

[0048] —NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0049] —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0050] —O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0051] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,

[0052] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—,

[0053] —C(R⁹R¹⁰)—NR²—C(O)—O—,

[0054] —C(R⁹R¹⁰)—O—C(O)—NR²,

[0055] —C(R⁹R¹⁰)—NR²—C(O)—NR²—,

[0056] —NR²—C(O)—O—C(R⁹R¹⁰)—,

[0057] —NR²—C(O)—NR²—C(R⁹R¹⁰)—,

[0058] —NR²—S(O)₂—NR²—C(R⁹R¹⁰)—,

[0059] —O—C(O)—NR²—C(R⁹R¹⁰)—,

[0060] —C(O)—N═C(R¹¹)—NR²—,

[0061] —C(O)—NR²—C(R¹¹)═N—,

[0062] —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—,

[0063] —NR¹²—C(R⁹R¹⁰)—,

[0064] —NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0065] —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0066] —NR²—C(R¹¹)═N—C(O)—,

[0067] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,

[0068] —C(R⁹R¹⁰)—NR¹²—,

[0069] —N═C(R¹¹)—NR²—C(O)—,

[0070] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,

[0071] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—,

[0072] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,

[0073] —C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,

[0074] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,

[0075] —O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0076] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—,

[0077] —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,

[0078] —C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and

[0079] —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—;

[0080] Q is a covalent bond or CH₂;

[0081] W is CH or N;

[0082] X is CR⁹R¹⁰, C═CH₂ or C═O;

[0083] Y is CR⁹R¹⁰, O or NR²;

[0084] Z is C═O, C═S or S(O)₂;

[0085] G¹ is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl,carboxyl, —CONH₂, —(C₁-C₄)alkyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, —(C₁-C₄)alkoxy optionally independently substituted with one ormore phenyl, one or more halogens or one or more hydroxy groups,—(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl, N,N-di-(C₁-C₄)alkylamino,—(C₂-C₆)alkenyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,—(C₂-C₆)alkynyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,—(C₃-C₆)cycloalkyl optionally independently substituted with one or more(C₁-C₄)alkyl groups, one or more halogens or one or more hydroxy groups,—(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl;

[0086] G² and G³ are each independently selected from the groupconsisting of hydrogen, halo, hydroxy, —(C₁-C₄)alkyl optionallyindependently substituted with one to three halo groups and—(C₁-C₄)alkoxy optionally independently substituted with one to threehalo groups;

[0087] R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

[0088] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

[0089] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C═C—, —N(X⁶)C(O)—,—C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0090] q is 0, 1, 2, 3 or 4;

[0091] t is 0, 1, 2 or 3;

[0092] said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹are optionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

[0093] R^(1A) is selected from the group consisting of hydrogen, F, Cl,Br, I, (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″;

[0094] R² is hydrogen, (C₁-C₈)alkyl, —(C₀C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl—A¹ or A¹;

[0095] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxy, —C(O)OX⁶,—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 independently selected halo groups;

[0096] R³ is selected from the group consisting of A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹—(C₀-C₅)alky-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

[0097] where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5independently selected halo groups or 1, 2 or 3 independently selected—OX³ groups;

[0098] X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

[0099] R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cydoalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

[0100] X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴and the nitrogen atom to which X⁴ is attached and the carbon atom towhich R⁴ is attached and form a five to seven membered ring;

[0101] R⁶ is a bond or is

[0102] where a and b are each independently 0, 1, 2 or 3;

[0103] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, CF₃, A¹ and optionally substituted (C₁-C₆)alkyl;

[0104] the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with a substituent selected fromthe group consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

[0105] or the carbon bearing X⁵ or X^(5a) forms one or two alkylenebridges with the nitrogen atom bearing R⁷ and R⁸ wherein each alkylenebridge contains 1 to 5 carbon atoms, provided that when one alkylenebridge is formed then only one of X⁵ or X^(5a) is on the carbon atom andonly one of R⁷ or R⁸ is on the nitrogen atom and further provided thatwhen two alkylene bridges are formed then X⁵ and X^(5a) cannot be on thecarbon atom and R⁷ and R⁸ cannot be on the nitrogen atom;

[0106] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

[0107] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a bicyclic ring system consisting of apartially saturated or fully saturated 5- or 6-membered ring, optionallyhaving 1 or 2 heteroatoms independently selected from the groupconsisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

[0108] Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O;

[0109] R⁷ and R⁸ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl;

[0110] where the optionally substituted (C₁-C₆)alkyl in the definitionof R⁷ and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groups or 1 to 3(C₁-C₆)alkoxy groups; or

[0111] R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

[0112] where L is C(X²)(X²), S(O)_(m) or N(X²);

[0113] R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionallyindependently substituted with 1-5 halo groups;

[0114] R¹¹ is selected from the group consisting of (C₁-C₅)alkyl andphenyl optionally substituted with 1-3 substitutents each independentlyselected from the group consisting of (C₁-C₅)alkyl, halo and(C₁-C₅)alkoxy;

[0115] R¹² is selected from the group consisting of(C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkyl where the alkylportion is optionally independently substituted by 1-5 halo groups;

[0116] A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

[0117] A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶) , —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂)NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

[0118] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0119] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to 3(C₁-C₆)alkoxy groups;

[0120] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, the X¹² groupis optionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0121] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—;

[0122] L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0123] r for each occurrence is independently 1, 2 or 3;

[0124] X² for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl or optionally substituted (C₃-C₇)cycloalkyl,where the optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or1-3 OX³ groups;

[0125] X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0126] X⁶ for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionallysubstituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, whereoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlymono- or di-substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl esteror 1H-tetrazol-5-yl; or

[0127] when there are two X⁶ groups on one atom and both X⁶ areindependently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4 to 9- membered ring optionally having oxygen,sulfur or NX⁷ as a ring member;

[0128] X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted withhydroxy;

[0129] m for each occurrence is independently 0, 1 or 2;

[0130] with the proviso that:

[0131] X⁶ and X¹² cannot be hydrogen when attached to C(O) or S(O)₂ inthe form C(O)X⁶, C(O)X¹², S(O)₂X⁶ or S(O)₂X¹²; and

[0132] when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

[0133] From herein on, the word “compounds” includes a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug unless otherwise more specifically stated.

[0134] A preferred group of the foregoing compounds, designated the AGroup compounds, are those compounds of formula I wherein

[0135] R⁴ is hydrogen or methyl; X⁴ is hydrogen;

[0136] R⁶ is

[0137] where Z¹ is a bond and a is 0 or 1; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen, CF₃,phenyl and optionally substituted (C₁-C₆)alkyl;

[0138] where the optionally substituted (C₁-C₆)alkyl in the definitionof X⁵ and X^(5a) is optionally substituted with OX² or A¹;

[0139] where A¹ in the definition of X⁵ and X^(5a) is imidazolyl,phenyl, indolyl, p-hydroxyphenyl, (C₅-C₇)cycloalkyl,—S(O)_(m)(C₁-C₆)alkyl, —N(X²)(X²) or —C(O)N(X²)(X²);

[0140] R⁷ is hydrogen or (C₁-C₃)alkyl;

[0141] or X⁵ and R⁷ are taken together and form a (C₁-C₅)alkylenebridge; and

[0142] R⁸ is hydrogen or (C₁-C₃)alkyl optionally substituted with one ortwo hydroxy groups.

[0143] A group of compounds which is preferred among the A Groupcompounds, designated the B Group, are those compounds of the A Groupwherein b is 0; X⁵ and X^(5a) are each independently selected from thegroup consisting of hydrogen, (C₁-C₃)alkyl and hydroxy(C₁-C₃)alkyl; and

[0144] R³ is selected from the group consisting of thienyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—, 1-indolyl-CH₂—,2-indolyl-CH₂—, 3-indolyl-CH₂—, 1-naphthyl-CH₂, 2-naphthyl-CH₂—,1-benzimidazolyl-CH₂—, 2-benzimidazolyl-CH₂—, phenyl-(C₁-C₄)alkyl,2-pyridyl-(C₁-C₄)alkyl-, 3-pyridyl-(C₁-C₄)alkyl-,4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂-, thienyl-(C₁-C₄)alkyl-,phenyl-(C₀-C₃)alkyl-O—CH₂, phenyl-CH₂—O-phenyl—CH₂—, phenyl—O—CH₂— CH₂-and 3-benzothienyl-CH₂—;

[0145] where the aryl portion(s) of the groups defined for R³ are eachoptionally substituted with one to three substtuents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

[0146] A group of compounds which is preferred among the B Groupcompounds, designated the C Group, are those compounds of the B Groupwherein

[0147] R⁴ is hydrogen; a is 0;

[0148] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, methyl or hydroxymethyl, provided that when X⁵is hydrogen then X^(5a) is not hydrogen;

[0149] R⁷ and R⁸ are each hydrogen; and

[0150] R³ is selected from the group consisting of 3-indolyl-CH₂—,1-naphthyl-CH₂—, 2-naphthyl-CH₂—, phenyl-(C₁-C₄)alkyl-,2-pyridyl-(C₁-C₄)alkyl-, 3-pyridyl-(C₁-C₄)alkyl-,4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂—, thienyl-(C₂-C₄)alkyl-,phenyl-(C₀-C₃)alkyl-O-CH₂—, 3-benzothienyl-CH₂—, thienyl-CH₂—O—CH₂—,thiazolyl-CH₂—O—CH₂, pyridyl-CH₂—O—CH₂— and phenyl-O—CH₂—CH₂—;

[0151] where the aryl portion(s) of the groups defined for R³ are eachoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

[0152] A group of compounds which is preferred among the C Groupcompounds, designated the D Group, are those compounds of the C Groupwherein

[0153] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0154] A² in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0155] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to3 fluoro atoms;

[0156] q is 1 or 2; t is 1 or 2;

[0157] R³ is phenyl-CH₂—O—CH₂—, phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂-,thienyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— or3-indolyl-CH₂—;

[0158] where the carbon atom bearing the substituent R³ is of the(R)-configuration;

[0159] where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; and

[0160] X⁵ and X^(5a) are each methyl.

[0161] A group of compounds which is preferred among the D Groupcompounds, designated the E Group, are those compounds of the D Groupwherein

[0162] HET is

[0163] A group of compounds which is preferred among the E Groupcompounds, designated the F Group, are those compounds of the E Groupwherein

[0164] Z is S(O)₂; Q is a covalent bond; X is CH₂; and

[0165] Y is CH₂ or NR²;

[0166] R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0167] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

[0168] A group of compounds which is preferred among the F Groupcompounds, designated the G Group, are those compounds of the F Groupwherein Y is CH₂.

[0169] A group of compounds which is preferred among the G Groupcompounds, designated the H Group, are those compounds of the G Groupwherein

[0170] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and

[0171] R³ is selected from the group consisting of 3-indolyl-CH₂,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

[0172] A preferred compound of the H Group is the 3a(R,S),1(R)diastereomeric mixture, the 3a(R),1(R) diastereomer or the 3a(S),1(R)diastereomer of 2-amino-N-[2-(3a-benzyl-1,1-dioxo-hexahydro-1-thia-5,7a-diaza-inden-5-yl)-1-benzyloxymethyl-2-oxo-ethylo-2-methyl-propionamide.

[0173] Another group of compounds which is preferred among the E Groupcompounds, designated the I Group, are those compounds of the E Groupwherein

[0174] Z is C═O; Q is a covalent bond; X is CH₂; and Y is NR²;

[0175] R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0176] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

[0177] A group of compounds which is preferred among the I Groupcompounds, designated the J Group, are those compounds of the I Groupwherein

[0178] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

[0179] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups; and

[0180] R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

[0181] A preferred compound of the J Group is the 8a(R,S),1(R)diastereomeric mixture, the 8a(R),1(R) diastereomer or the 8a(S),1(R)diastereomer of2-amino-N-[2-(8a-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.

[0182] Another group of compounds which is preferred among the E Groupcompounds, designated the K Group, are those compounds of the E Groupwherein

[0183] Z is C═O; Q is a covalent bond; X is CH₂; and Y is O.

[0184] A group of compounds which is preferred among the K Groupcompounds, designated the L Group, are those compounds of the K Groupwherein

[0185] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and

[0186] R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂-—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

[0187] A group of compounds which is preferred among the L Groupcompounds, designated the M Group, are where the compound is the8a(R,S),1(R) diastereomeric mixture, the 8a(R), 1(R) diastereomer or the8a(S),1(R) diastereomer of the compound selected from the groupconsisting of

[0188]2-amino-N-[2-(8a-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

[0189]2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-thiazol-4-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamideand

[0190]2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-3-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide.

[0191] Another group of compounds which is preferred among the E Groupcompounds, designated the N Group, are those compounds of the E Groupwherein

[0192] Z is C═O or S(O)₂; Q is a covalent bond; X is C═O; and Y is NR²;

[0193] R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0194] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

[0195] A group of compounds which is preferred among the N Groupcompounds, designated the O Group, are those compounds of the N Groupwherein

[0196] Z is C═O; R¹ is —CH₂—A¹, where A¹ in the definition of R¹ isphenyl or pyridyl where said phenyl or pyridyl is optionally substitutedwith one to three substituents, each substituent being independentlyselected from the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ andCF₃; and

[0197] R³ is phenyl-CH₂—O—CH₂—, pyridyl-CH₂—O—-CH₂—, phenyl-(CH₂)₃—,3-indolyl-CH₂— or thiazolyl-CH₂—O—CH₂—, where the aryl portion of thegroups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.

[0198] A group of compounds which is preferred among the O Groupcompounds, designated the P Group, are those compounds of the O Groupwherein

[0199] R² is hydrogen or (C₁-C₃)alkyl where the alkyl group isoptionally substituted with 1-3 fluoro groups.

[0200] A group of compounds which is preferred among the P Groupcompounds, designated the Q Group, are those compounds of the P Groupwherein

[0201] R³ is phenyl-CH₂—O—CH₂— or phenyl-(CH₂)₃—, where the phenyl inthe definition of R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.

[0202] A group of compounds which is preferred among the Q Groupcompounds, designated the R Group, are those compounds of the Q Groupwherein

[0203] R¹ is —CH₂—A¹ where A¹ is phenyl, 2-pyridyl, 3-pyridyl,optionally substituted with 1-3 fluoro groups or 1-3 Chloro groups;

[0204] R² is methyl or ethyl where the ethyl group is optionallysubstituted with 1-3 fluoro groups; and

[0205] R³ is phenyl-CH₂—O—CH₂—, where the phenyl is optionallysubstituted with 1-3 fluoro groups, 1-3 Chloro groups or 1-2 CF₃ groups.

[0206] A preferred compound of the R Group is the 1(R),8a(R,S)diastereomeric mixture, the 1(R),8a(R) diastereomer or the 1(R),8a(S)diastereomer of2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-pyridin-3-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

[0207] A group of compounds which is preferred among the R Groupcompounds, designated the S Group, are those compounds of the R Groupwherein

[0208] R¹ is —CH₂—A¹ where A¹ is phenyl optionally substituted with 1-2chloro groups or 1-2 fluoro groups;

[0209] R² is methyl or —CH₂CF₃; and

[0210] R³ is phenyl-CH₂—O—CH₂—, optionally substituted with 1-3 fluorogroups, 1-3 chloro groups or 1-2 CF₃ groups.

[0211] A group of compounds which is preferred among the S Groupcompounds, designated the T Group, are those compounds of the S Groupwhere the compound is selected from the group consisting of

[0212]2-amino-N-[2-(8a-(R,S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

[0213]2-amino-N-(1-(R)-benzyloxymethyl-2-[8a-(R,S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxohexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl)2-methyl-propionamideand

[0214]2-amino-N-{2-[8a-(R,S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]--(R)-benzyloxymethyl-2-oxo-ethyl}2-methyl-propionamide.

[0215] The following compounds are particularly preferred of the T Groupcompounds:

[0216]2-amino-N-[2-(8a-(R)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo(1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;

[0217]2-amino-N-[2-(8a-(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;

[0218]2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide;

[0219]2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide;

[0220]2-amino-N-{2-[8a-(R)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-l-(R)-benzyloxymethyl-2-oxo-ethyl}2-methyl-propionamide;and

[0221]2-amino-N-{2-[8a-(S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-l-(R)-benzyloxymethyl-2-oxo-ethyl}2-methyl-propionamide.

[0222] Another group of compounds which is preferred among the R Groupcompounds, designated the U Group, are those compounds of the R Groupwherein

[0223] R¹ is —CH₂—A¹ where A¹ is 2-pyridyl optionally substituted with1-2 chloro groups;

[0224] R² is methyl or —CH₂CF₃; and

[0225] R³ is phenyl-CH₂—O—CH₂—, optionally substituted with 1-3 fluorogroups, 1-3 chloro groups or 1-2 CF₃ groups.

[0226] A group of compounds which is preferred among the U Groupcompounds, designated the V Group, are those compounds of the U Groupwhere the compound is

[0227]2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,

[0228]2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide,

[0229] 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trfluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,

[0230] 2-amino-N-[2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamideor

[0231]2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

[0232] The following compounds are particularly preferred of the V Groupcompounds:

[0233]2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide;

[0234]2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide;

[0235]2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

[0236]2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2.2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide;

[0237]2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

[0238]2-amino-N-{1-(R)-(2,4-difluoro-benzyioxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-tdfluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide;

[0239]2-amino-N-[2-[1,3-dioxo-8a-(R)-pyddin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide;

[0240]2-amino-N-[2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide;

[0241]2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide;and

[0242]2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

[0243] Another group of compounds which is preferred among the E Groupcompounds, designated the W Group, are those compounds of the E Groupwherein

[0244] Z is C═O; Q is a covalent bond; X is C═O; and Y is CH₂.

[0245] A group of compounds which is preferred among the W Groupcompounds, designated the X Group, are those compounds of the W Groupwherein

[0246] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of fluoro,chloro, methyl, OCH₃, OCF₂H, OCF₃ and CF₃; and R³ is selected from thegroup consisting of 3-indolyl-CH₂—, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂—and thiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups definedfor R³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

[0247] A preferred compound of the X Group is the 1(R), 8a(R,S)diastereomeric mixture, the 1(R),8a(R) diastereomer or the 1(R),8a(S)diastereomer of2-amino-N-{1-benzyloxymethyl-2-[8a-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl} 2-methyl-propionamide.

[0248] Another group of compounds which is preferred among the D Groupcompounds, designated the Y Group, are those compounds of the D Groupwherein HET is

[0249] A group of compounds which is preferred among the Y Groupcompounds, designated the Z Group, are those compounds of the Y Groupwherein

[0250] W is N; d is 1; e is 0 or 1;

[0251] R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0252] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups;

[0253] G¹ is hydrogen, halo, hydroxy, —(C₁-C₂)alkyl optionallyindependently substituted with one to three halo groups or—(C₁-C₂)alkoxy optionally independently substituted with one to threehalo groups;

[0254] G² is hydrogen, halo, hydroxy, —(C₁-C₂)alkyl optionallyindependently substituted with one to three halo groups or—(C₁-C₂)alkoxy optionally independently substituted with one to threehalo groups; and

[0255] G³ is hydrogen.

[0256] A group of compounds which is preferred among the Z Groupcompounds, designated the M Group, are those compounds of the Z Groupwherein

[0257] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups;

[0258] R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

[0259] G¹, G² and G³ are each independently hydrogen, Cl or F.

[0260] A preferred compound of the M Group is2-amino-N-[1-(R)-(lH-indol-3-ylmethyl)-2-oxo-2-(9-oxo-1,2,4a,9-tetrahydro-4H-3,9a-diaza-fluoren-3-yl)-ethyl]-2-methyl-propionamide.

[0261] Another group of compounds which is preferred among the C Groupcompounds, designated the AB Group, are those compounds of the C Groupwherein

[0262] HET is

[0263] A group of compounds which is preferred among the AB Groupcompounds, designated the AC Group, are those compounds of the AB Groupwherein

[0264] X⁵ and X⁵a are each methyl; d is 1; e is 1;

[0265] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0266] A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0267] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to3 fluoro groups;

[0268] t is 1 or2; q is 1 or 2; and

[0269] R² is hydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0270] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups.

[0271] A group of compounds which is preferred among the AC Groupcompounds, designated the AD Group, are those compounds of the AC Groupwherein

[0272] R¹ is (C₁-C₆)alkyl optionally substituted with 1-3 fluoro groups;

[0273] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups; and

[0274] R³ is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)₃—, phenyl-CH₂O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH3, OCH₃, OCF₃,OCF₂H and CF₃.

[0275] A preferred compound of the AD Group is2-amino-N-[2-(2,3-dimethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]2-methyl-propionamide.

[0276] Another group of compounds which is preferred among the D Groupcompounds, designated the AE Group, are those compounds of the D Groupwherein

[0277] HET is

[0278] A group of compounds which is preferred among the AE Groupcompounds, designated the AF Group, are those compounds of the AE Groupwherein

[0279] A is —NR²—C(O)—O—; d is 1; e is 1;

[0280] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0281] A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0282] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3fluoro groups;

[0283] tis 1 or 2; q is 1 or 2;

[0284] R^(1A) is hydrogen or methyl; and

[0285] R² is hydrogen, (C₁-C₅)alkyl, —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl or(C₁-C₂)alkyl-A¹, where A¹ in the definition of R² is pyridyl;

[0286] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups.

[0287] A group of compounds which is preferred among the AF Groupcompounds, designated the AG Group, are those compounds of the AF Groupwherein

[0288] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

[0289] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups;

[0290] R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

[0291] R^(1A) is hydrogen.

[0292] A group of compounds which is preferred among the AG Groupcompounds, designated the AH Group, are those compounds of the AG Groupwhere the compound is the 3a(R,S)-7a(R,S) diastereomeric mixture, the3a(R),7a(R) diastereomer, the 3a(S),7a(S) diastereomer, the 3a(R),7a(S)diastereomer or the 3a(S),7a(R) diastereomer of the compound selectedfrom the group consisting of3a-7a-2-amino-N-[2-(3a-benzyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-3-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[2-(3a-benzyl-3-methyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-propionamideand3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-oxo-2-(2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide.

[0293] Another group of compounds which is preferred among the AE Groupcompounds, designated the Al Group, are those compounds of the AE Groupwherein

[0294] A is —C(O)—NR²—CH₂—, —C(O)—O—CH₂—, —C(O)—NR²-C(O)-₁ -CH₂NR¹²—CH₂or —C(O)—NR²—CH₂CH₂—;

[0295] d is 1; e is 1;

[0296] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0297] A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0298] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3fluoro groups;

[0299] t is 1 or 2; q is 1 or 2;

[0300] R^(1A) is hydrogen or methyl; and

[0301] R² is hydrogen, (C₁-C₅)alkyl, —(C₀-C₂)alkyl-(C₃-C₈)cydoalkyl;

[0302] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups.

[0303] A group of compounds which is preferred among the Al Groupcompounds, designated the AJ Group, are those compounds of the Al Groupwherein

[0304] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

[0305] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups; and

[0306] R³is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

[0307] R^(1A) is hydrogen.

[0308] A group of compounds which is preferred among the AJ Groupcompounds, designated the AK Group, are those compounds of the AJ Groupwhere the compound is selected from the group consisting of

[0309]2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,

[0310] the 3a(R,S), 1(R) diastereomeric mixture, the 3a(R), 1 (R)diastereomer or the 3a(S), 1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

[0311] the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R)diastereomer or the 3a(S), 1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-hexahydro-furo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,

[0312] the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R)diastereomer or the 3a(S), 1(R) diastereomer ofN-[2-(2-acetyl-3a-benzyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-(1H-indol-2-ylmethyl)-2-oxo-ethyl]-2-amino-2-methyl-propionamideand

[0313] the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R)diastereomer or the 8a(S), 1(R) diastereomer of2-amino-N-[2-(8a-benzyl-7-methyl-8-oxo-octahydro-[2,7]naphthyridin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.

[0314] Another group of compounds which is preferred among the AE Groupcompounds, designated the AL Group, are those compounds of the AE Groupwherein

[0315] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0316] A¹ in the definition of R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0317] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, or 1-3fluoro groups;

[0318] t is 1 or 2; q is 1 or 2;

[0319] R^(1A) is hydrogen or methyl;

[0320] R² is hydrogen, (C₁-C₅)alkyl or -(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;

[0321] where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1-3 fluoro groups;

[0322] d is 1; e is 1; and

[0323] R⁹ and R¹⁰ are each hydrogen.

[0324] A group of compounds which is preferred among the AL Groupcompounds, designated the AM Group, are those compounds of the AL Groupwherein

[0325] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F. Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

[0326] R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups; and

[0327] R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and

[0328] R^(1A) is hydrogen.

[0329] Another group of compounds which is preferred among the C Groupcompounds, designated the AN Group, are those compounds of the C Groupwherein

[0330] HET is

[0331] Z is C═O or S(O)₂; Q is a covalent bond; X is C═O; Y is NR²;

[0332] R² is hydrogen, (C₁-C₅)alkyl or -(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R² areoptionally substituted with 1, 2 or 3 fluoro groups;

[0333] R¹ is hydrogen; and

[0334] R³ is selected from the group consisting of phenyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)₃—, 3-indolyl-CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

[0335] A group of compounds which is preferred among the AN Groupcompounds, designated the AO Group, are those compounds of the AN Groupwherein Z is C═O; R² is hydrogen or (C₁-C₃)alkyl optionally substitutedwith 1-3 fluoro groups.

[0336] A group of compounds which is preferred among the AO Groupcompounds, designated the AP Group, are those compounds of the AO Groupwherein R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.

[0337] A preferred compound of the AP Group is8a-(R,S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0338] An even more preferred compound of the AP Group is8a-(R)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0339] Another more preferred compound of the AP Group is8a-(S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0340] This invention also provides:

[0341] methods for increasing levels of endogenous growth hormone in ahuman or other animal such as especially dogs, cats and horses, whichcomprise administering to such human or other animal an effective amountof a compound of Formula I;

[0342] pharmaceutical compositions which comprise a pharmaceuticallyacceptable carrier and an effective amount of a compound of Formula I;

[0343] pharmaceutical compositions useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprise a pharmaceutically acceptable carrier, an effective amount of acompound of Formula I and a growth hormone secretagogue selected fromthe group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormonereleasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof;

[0344] methods for treating or preventing osteoporosis and/or frailtywhich comprise administering to a human or other animal especially dogs,cats and horses, in need of such treatment or prevention an amount of acompound of Formula I which is effective in treating or preventingosteoporosis and/or frailty;

[0345] methods for treating or preventing diseases or conditions whichmay be treated or prevented by growth hormone which compriseadministering to a human or other animal in need of such treatment orprevention an amount of a compound of Formula I which is effective inpromoting release of endogenous growth hormone;

[0346] preferred methods of the immediately foregoing methods is wherethe disease or condition is congestive heart failure, frailty associatedwith aging or obesity;

[0347] preferred methods of the immediately foregoing methods is wherethe disease or condition is congestive heart failure or frailtyassociated with aging;

[0348] methods for accelerating bone fracture repair, attenuatingprotein catabolic response after a major operation, reducing cachexiaand protein loss due to chronic illness such as AIDS or cancer,accelerating wound healing, or accelerating the recovery of bum patientsor patients having undergone major surgery, which methods compriseadministering to a mammal in need of such treatment an amount of acompound of Formula I which is effective in promoting release ofendogenous growth hormone;

[0349] preferred methods of the immediately foregoing methods is foraccelerating the recovery of patients having undergone major surgery orfor accelerating bone fracture repair;

[0350] methods for improving muscle strength, mobility, maintenance ofskin thickness, metabolic homeostasis or renal homeostasis, whichmethods comprise administering to a human or other animal in need ofsuch treatment an amount of a compound of Formula I which is effectivein promoting release of endogenous growth hormone;

[0351] methods for the treatment or prevention of osteoporosis and/orfrailty which comprises administering to a human or other animalespecially dogs, cats and horses, with osteoporosis and/or frailtyeffective amounts of a bisphosphonate compound and a compound of FormulaI;

[0352] preferred methods of the immediately foregoing methods is wherethe bisphosphonate compound is alendronate or ibandronate;

[0353] methods for the treatment or prevention of osteoporosis and/orfrailty which comprise administering to a human or other animalespecially dogs, cats and horses, with osteoporosis and/or frailtyeffective amounts of estrogen or Premarin® and a compound of Formula Iand, optionally, progesterone;

[0354] methods for the treatment of osteoporosis and/or frailty whichcomprise administering to a human or other animal especially dogs, catsand horses, with osteoporosis and/or frailty effective amounts ofcalcitonin and a compound of Formula I;

[0355] methods to increase IGF-1 levels in a human or other animalespecially dogs, cats and horses, deficient in IGF-1 which compriseadministering to a human or other animal with IGF-1 deficiency acompound of Formula I;

[0356] methods for the treatment of osteoporosis and/or frailty whichcomprises administering to a human or other animal especially dogs, catsand horses, with osteoporosis and/or frailty effective-amounts of anestrogen agonist or antagonist and a compound of Formula I;

[0357] preferred methods of the immediately foregoing methods is wherethe estrogen agonist or antagonist is tamoxifen, droloxifene,raloxifene, idoxifene,cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline.

[0358] methods for enhancing growth and improving carcass quality of ananimal other than humans which comprise administering to said animal aneffective amount of a compound of Formula I;

[0359] methods for enhancing feed efficiency in an animal other thanhumans which comprise administering to said animal an effective amountof a compound of Formula I;

[0360] methods for increasing milk production in a female mammal whichcomprise administering to said female mammal an effective amount of acompound of Formula I;

[0361] methods for increasing piglet number, increasing pregnancy ratein sows, increasing viability of piglets, increasing weight of pigletsor increasing muscle fiber size in piglets which comprise administeringto a sow or piglet an effective amount of a compound of Formula I;

[0362] methods for increasing muscle mass, which comprise administeringto a human or other animal such as dogs, cats, horses, cattle, pigs,chickens, turkeys, sheep and fish, in need of such treatment an amountof a compound of Formula I;

[0363] methods for promoting growth in growth hormone deficient childrenwhich comprise administering to a growth hormone deficient child acompound of Formula I;

[0364] methods for the treatment or prevention of congestive heartfailure, obesity or frailty associated with aging, which compriseadministering to a human or other animal in need thereof effectiveamounts of a functional somatostatin antagonist and a compound ofFormula I;

[0365] preferred methods of the immediately foregoing methods is wherethe functional somatostatin antagonist is an alpha-2 adrenergic agonistand the other animal is a dog, cat or a horse;

[0366] preferred methods of the immediately foregoing methods is wherethe alpha-2 adrenergic agonist is clonidine, xylazine or medetomidine.

[0367] methods for treating insulin resistance in a mammal, whichcomprises administering to said mammal an effective amount of a compoundof Formula I;

[0368] preferred methods of the immediately foregoing methods is wherethe condition associated with insulin resistance is type I diabetes,type II diabetes, hyperglycemia, impaired glucose tolerance or aninsulin resistant syndrome; or where the condition associated withinsulin resistance is associated with obesity or old age;

[0369] methods for increasing the endogenous production or release ofgrowth hormone in a human or other animal especially dogs, cats andhorses, which comprise administering effective amounts of a compound ofFormula I and a growth hormone secretagogue selected from the groupconsisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor(GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof;

[0370] pharmaceutical compositions useful for treating or preventingosteoporosis and/or frailty which comprise a pharmaceutically acceptablecarrier, an amount of a bisphosphonate compound and an amount of acompound of Formula I;

[0371] pharmaceutical compositions useful for treating or preventingosteoporosis and/or frailty which comprises a pharmaceuticallyacceptable carrier, an amount of estrogen or Premarin®, an amount of acompound of Formula I and, optionally, an amount of progesterone;

[0372] pharmaceutical compositions useful for treating osteoporosisand/or frailty which comprise a pharmaceutically acceptable carrier, anamount of calcitonin and an amount of a compound of Formula I;

[0373] pharmaceutical compositions useful for treating preventingcongestive heart failure, obesity or frailty associated with aging,which comprise a pharmaceutically acceptable carrier, an amount of analpha-2 adrenergic agonist and an amount of a compound of Formula I;

[0374] a preferred pharmaceutical composition of the immediatelyforegoing compositions is where the alpha-2 adrenergic agonist isclonidine, xylazine or medetomidine; and

[0375] methods for increasing levels of endogenous growth hormone, whichcomprise administering to a human or other animal in need thereofeffective amounts of a functional somatostatin antagonist and a compoundof Formula I.

[0376] In yet another aspect, this invention provides methods forimproving muscle strength, niobility, maintenance of skin thickness,metabolic homeostasis and renal homeostasis, which compriseadministering to a human or other animal especially dogs, cats andhorses, in need of such treatment an amount of a compound of claim 1which is effective in promoting release of endogenous growth hormone.

[0377] The instant compounds promote the release of growth hormone whichare stable under various physiological conditions and may beadministered parenterally, nasally or by the oral route.

[0378] Another group of compounds which is preferred within the E Groupcompounds, designated the EA Group, comprises those compounds, orstereolsomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

[0379] Z is C═O; Q is a covalent bond;

[0380] Y is CR⁹R¹⁰

[0381] where R⁹ in the definition of Y is selected from the groupconsisting of hydrogen, fluoro, hydroxy and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups; and R¹⁰ in the definition of Y isselected from the group consisting of hydrogen, fluoro, and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups with the proviso that R¹⁰cannot be fluoro when R⁹ is hydroxy;

[0382] and X is CHR⁹

[0383] where R⁹ in the definition of X is selected from the groupconsisting of hydrogen, fluoro, hydroxy and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups.

[0384] A group of compounds which is preferred within the EA Groupcompounds, designated the EB Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

[0385] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and

[0386] R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃.

[0387] A group of compounds which is preferred within the EB Groupcompounds, designated the EC Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein

[0388] X is CH₂;

[0389] Y is CR⁹R¹⁰

[0390] where R⁹ and R¹⁰ in the definition of Y are independentlyselected from the group consisting of hydrogen, fluoro, and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups.

[0391] A group of compounds which is preferred within the EC Group,designated the ED Group, comprises those compounds or prodrugs of suchcompounds or pharmaceutically acceptable salts of the compounds orprodrugs wherein the compound is the 8a(R,S),1(R) diastereomericmixture, the 8a(R),1(R) diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-[2-(8a-benzyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamideor2-amino-N-[1-benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethyl]-2-methyl-propionamide.

[0392] Another group of compounds which is preferred within the J Groupcomprises those compounds or prodrugs of such compounds orpharmaceutically acceptable salts of the compounds or prodrugs whereinthe compound is the 8a(R,S),1(R) diastereomeric miture, the 8a(R),1(R)diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-{1-benzyloxymethyl-2-oxo-2-[3-oxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-ethyl}-2-methyl-propionamide;2-amino-N-{1-benzyloxymethyl-2-[8a-(2,4-difluoro-benzyl)-3-oxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl)}-2-methyl-propionamide;2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide;or2-amino-N-[1-benzyloxymethyl-2-(2-ethyl-3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0393] Another group of compounds which is preferred within the Q Groupcompounds, designated the QA Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

[0394] R¹ is —CH₂—A¹ where A¹ is phenyl, 2-pyridyl, or 3-pyridyl,optionally substituted with 1-3 F, 1-3 Cl;

[0395] R² is methyl or ethyl where the ethyl group is optionallysubstituted with 1-3 F; and

[0396] R³ is phenyl-(CH₂)₃-, where the phenyl is optionally substitutedwith 1-3 F. 1-3 Cl or 1-2 CF₃;

[0397] A group of compounds which is preferred within the QA Group ofcompounds, designated the QB Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein R¹ is —(CH₂)—A¹ where A¹ is2-pyridyl, optionally substituted with 1-2 Cl; and

[0398] R² is methyl or —CH₂CF₃.

[0399] A group of compounds which is preferred within the QB Group ofcompounds, designated the QC Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs wherein the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

[0400] An especially preferred compound within the QC Group comprisesthe compound or prodrugs of such compound or pharmaceutically acceptablesalts of the compound or prodrugs where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

[0401] Another especially preferred compound within the QC Groupcomprises the compound or prodrugs of such compound or pharmaceuticallyacceptable salts of the compound or prodrugs where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.

[0402] Another group of compounds which is preferred within the Al Groupof compounds, designated the Al^(A) Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

[0403] A is —C(O)—NR²—CH₂—;

[0404] R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each subsfituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃;

[0405] R² is hydrogen or —(C₁-C₃)alkyl or—(C₀-C₂)alkyl-(C₃-C₅)cycloalkyl where the alkyl and cycloalkyl groups inthe definition of R² are optionally substituted with 1-3 fluoro groups;

[0406] R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and

[0407] R^(1A) is hydrogen.

[0408] A group of compounds which is preferred within the Al^(A) Groupof compounds, designated the Al^(B) Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs where the compound is the 3a(R,S),7a(R,S)diastereomeric mixture, the 3a(R),7a(R) diastereomer, the 3a(S),7a(S)diastereomer, the 3a(R),7a(S) diastereomer, or the 3a(S),7a(R)diastereomer of2-amino-N-[2-(3a-benzyl-2-cyclopropyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;or2-amino-N-[1(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-pyridin-2-ylmethyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0409] This invention also provides compounds of the formula

[0410] or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceubcally acceptable salt of the compound, mixture,isomer or prodrug,

[0411] wherein

[0412] HET is a heterocyclic moiety selected from the group consistingof

[0413] d is 0, 1 or 2;

[0414] e is 1 or 2;

[0415] A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of

[0416] —C(R⁹R¹⁰)—NR²—C(O)—,

[0417] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0418] —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0419] —C(R⁹R¹⁰)—O—C(O)—,

[0420] —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—,

[0421] —NR²—C(O)—C(R⁹R¹⁰)—,

[0422] —O—C(O)—C(R⁹R¹⁰)—,

[0423] —C(R⁹R¹⁰)—C(O)—NR²—,

[0424] —C(R⁹R¹⁰)—C(O)—O—,

[0425] —C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0426] —C(O)—O—C(R⁹R¹⁰)—,

[0427] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0428] —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0429] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—,

[0430] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—,

[0431] —NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0432] —NR²—S(O)₂—C(R⁹R¹)—C(R⁹R¹⁰)—,

[0433] —O—C(O)—C(R⁹R¹⁰)—C(R⁰⁹R¹⁰)—,

[0434] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,

[0435] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—,

[0436] —C(R⁹R¹⁰)—NR²—C(O)—O—,

[0437] —C(R⁹R¹⁰)—O—C(O)—NR²,

[0438] —C(R⁹R¹⁰)—NR²—C(O)—NR²—,

[0439] —NR²—C(O)—O—C(R⁹R¹⁰)—,

[0440] —NR²—C(O)—NR²—C(R⁹R¹⁰)—,

[0441] —NR²—S(O)₂—NR²—C(R⁹R¹⁰)—,

[0442] —O—C(O)—NR²—C(R⁹R¹⁰),

[0443] —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—,

[0444] —NR¹²—C(R⁹R¹⁰)—,

[0445] —NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0446] —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,

[0447] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,

[0448] —C(R⁹R¹)—NR¹²—,

[0449] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,

[0450] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—,

[0451] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,

[0452] —C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,

[0453] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,

[0454] —O—C(R⁹R¹⁰—C(R⁹R¹⁰)—,

[0455] —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—,

[0456] —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,

[0457] —C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and

[0458] —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—;

[0459] Q is a covalent bond or CH₂;

[0460] W is CH or N;

[0461] X is CR^(9a)R^(10a), C═CH₂ or C═O;

[0462] Y is CR⁹R¹⁰or NR²;

[0463] Z is C═O, C═S or S(O)₂;

[0464] R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,

[0465] —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)(S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,

[0466] —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹,

[0467] —(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶,

[0468] —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶),

[0469] —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,

[0470] —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹,

[0471] —(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl,—(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,

[0472] —(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or—(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

[0473] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

[0474] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—,—C(O)N)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0475] q is 0, 1, 2, 3 or 4;

[0476] t is 0, 1, 2 or 3;

[0477] said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹are optionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

[0478] R^(1A) is selected from the group consisting of hydrogen, F, Cl,Br, I, (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″;

[0479] R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

[0480] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxy, —C(O)OX⁶,—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 independently selected halo groups;

[0481] R³ is selected from the group consisting of A¹, (C₁-C₁₀)alkyl,—(C₁-C₆)alkyl-A¹, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl, —(C₁-C₅)alkyl-X¹—(C₀-C₅)alkyl-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

[0482] where the alkyl groups in the definition of R³ are optionallysubstituted with

[0483] —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independentlyselected halo groups or 1, 2 or 3 independently selected —OX³ groups;

[0484] X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

[0485] R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6membered ring, optionally having 1to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

[0486] X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴and the nitrogen atom to which X⁴ is attached and the carbon atom towhich R⁴ is attached and form a five to seven membered ring;

[0487] R⁶ is a bond or is

[0488] where a and b are each independently 0, 1, 2 or 3;

[0489] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, CF₃, A¹ and optionally substituted (C₁-C₆)alkyl;

[0490] the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with a substituent selected fromthe group consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

[0491] or the carbon bearing X⁵ or X^(5a) forms one or two alkylenebridges with the nitrogen atom bearing R⁷ and R⁸ wherein each alkylenebridge contains 1 to 5 carbon atoms, provided that when one alkylenebridge is formed then only one of X⁵ or X^(5a) is on the carbon atom andonly one of R⁷ or R⁸ is on the nitrogen atom and further provided thatwhen two alkylene bridges are formed then X⁵ and X^(5a) cannot be on thecarbon atom and R⁷ and R⁸ cannot be on the nitrogen atom;

[0492] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

[0493] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a bicyclic ring system consisting of apartially saturated or fully saturated 5- or 6-membered ring, optionallyhaving 1 or 2 heteroatoms independently selected from the groupconsisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

[0494] Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O;

[0495] R⁷ and R⁸ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl;

[0496] where the optionally substituted (C₁-C₆)alkyl in the definitionof R⁷ and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groups or 1 to 3(C₁-C₆)alkoxy groups; or

[0497] R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

[0498] where L is C(X²)(X²), S(O)_(m) or N(X²);

[0499] R⁹, R^(9a), R¹⁰ and R^(10a) are each independently hydrogen,fluoro, hydroxy, (C₁-C₄)alkoxy or (C₁-C₅)alkyl optionally substitutedwith 1 to 5 halogroups, provided that at least one of R⁹, R^(9a), R¹⁰ orR^(10a) is present and is (C₁-C₄)alkoxy;

[0500] R¹¹ is selected from the group consisting of (C₁-C₅)alkyl andphenyl optionally substituted with 1-3 substitutents each independentlyselected from the group consisting of (C₁-C₅)alkyl, halo and(C₁-C₅)alkoxy;

[0501] R¹² is selected from the group consisting of(C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkyl where the alkylportion is optionally independently substituted by 1-5 halo groups;

[0502] A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

[0503] A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5yl, phenyl, phenoxy, phenylalkyloxy,halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —S(O)₂N(X⁶)(X⁶),—N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹², —S(O)₂NX¹¹X¹²,—NX⁶S(O)₁₂X², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy;

[0504] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0505] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to 3(C₁-C₆)alkoxy groups;

[0506] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, the X¹² groupis optionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0507] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—;

[0508] L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0509] r for each occurrence is independently 1, 2 or 3;

[0510] X² for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl or optionally substituted (C₃-C₇)cycloalkyl,where the optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or1-3 OX³ groups;

[0511] X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0512] X⁶ for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionallysubstituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, whereoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlymono- or di-substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl esteror 1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom andboth X⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups maybe optionally joined and, together with the atom to which the two X⁶groups are attached, form a 4 to 9- membered ring optionally havingoxygen, sulfur or NX⁷ as a ring member,

[0513] X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted withhydroxy;

[0514] m for each occurrence is independently 0, 1 or 2;

[0515] with the proviso that:

[0516] X⁶ and X¹² cannot be hydrogen when attached to C(O) or S(O)₂ inthe form C(O)X⁶, C(O)X¹², S(O)₂X⁶ or S(O)₂X¹²; and

[0517] when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r), is independently 2 or 3.

[0518] A preferred group of compounds within the scope of the compoundsdisclosed in the immediately preceding paragraph, designated the ZAGroup, comprises those compounds or a stereoisomeric mixtures thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomers thereof, or prodrugs of suchcompounds, mixtures or isomers thereof, or pharmaceutically acceptablesalts of the compounds. mixtures, isomers or prodrugs wherein:

[0519] HET is

[0520] R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or(C₁-C₁₀)alkyl;

[0521] where A¹ in the definition or R¹is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃;

[0522] the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to3 fluoro atoms;

[0523] q is 1 or2;

[0524] t is 1 or 2;

[0525] R³ is selected form the group consisting of phenyl-CH₂—O—CH₂—,phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂—, thienyl-CH₂—O—CH₂—,3-indolyl-CH₂—, phenyl-(CH₂)₃—and thiazolyl-CH₂—O—CH₂—; where the carbonatom bearing the substituent R³ is of the (R)-configuration;

[0526] where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃

[0527] R⁴ is hydrogen;

[0528] R⁶ is

[0529] where Z¹ is a bond; X⁵ and X^(5a) are each methyl; a and b areeach 0;

[0530] R⁷ and R⁸ or each hydrogen;

[0531] X⁴ is hydrogen.

[0532] A group of compounds which is preferred within the ZA Group ofcompounds, designated the ZB Group, comprises those compounds orstereoisomeric mixtures thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomers thereof, or prodrugs of such compounds, mixtures or isomersthereof, or pharmaceutically acceptable salts of the compounds,mixtures, isomers or prodrugs wherein:

[0533] Z is C═O; Q is a covalent bond;

[0534] Y is CR⁹R¹⁰

[0535] where R⁹ in the definition of Y is selected from the groupconsisting of hydrogen, fluoro, hydroxy, (C₁-C₂)alkoxy and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups; and R¹⁰ in the definitionof Y is selected from the group consisting of hydrogen, fluoro, and(C₁-C₂)alkyl optionally substituted with 1-3 fluoro groups with theproviso that R¹⁰ cannot be fluoro when R⁹ is hydroxy or (C₁-C₂)alkoxy;

[0536] and X is CHR^(9a)

[0537] where R⁹ in the definition of X is selected from the groupconsisting of hydrogen, fluoro, hydroxy, (C₁-C₂)alkoxy and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups.

[0538] R¹ is —CH₂—A¹

[0539] where A¹ is phenyl, pyridyl or thiazolyl, optionally substitutedwith one to three substituents, each substituent being independentlyselected from the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ andCF₃; and

[0540] R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—,

[0541] where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃.

[0542] A group of compounds which is preferred within the ZB Group ofcompounds, designated the ZC Group, comprises those compounds orprodrugs of such compounds or pharmaceutically acceptable salts of thecompounds or prodrugs where the compound is the 8(R,S),8a(R,S)diastereomeric mixture, the 8(R),8a(R) diastereomer, the 8(S),8a(S)diastereomer, the 8(R),8a(S) diastereomer, or the 8(S), 8a(R)diastereomer of 2-amino-N-[1(R)-benzyloxymethyl-2-(8-methoxy-6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-2-oxo-ethyl]-2-methyl-propionamide.

[0543] This invention also provides methods of treating or preventingsleep disorders in a mammal, including humans or other animals such asespecially dogs, cats and horses, which comprise administereing to suchhuman or other animal an effective amount of a compound of Formula I.

[0544] This invention also provides the L-tartrate salt of2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-alpyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.

[0545] This invention also provides compounds of the formula

[0546] where R¹ is hydrogen, —CN, —(CH₂)_(q)N(X)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

[0547] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

[0548] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—,—C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0549] m for each occurrence is 0, 1 or 2;

[0550] q is 0, 1, 2, 3 or 4;

[0551] t is 0, 1, 2 or 3;

[0552] said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹are optionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

[0553] A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

[0554] A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶))C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

[0555] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0556] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to 3(C₁-C₆)alkoxy groups;

[0557] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, the X¹² groupis optionally substituted with one to three subsfituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0558] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—;

[0559] L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0560] X⁶ for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionallysubstituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, whereoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlymono- or di-substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, CONH₂,

[0561] —S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; and

[0562] R² is hydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹;

[0563] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxy, —C(O)OX⁶,—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 independently selected halo groups.

[0564] A group of compounds which is preferred within the compoundsdisclosed within the immediately preceding paragraph, designated the XAGroup, comprises those compounds wherein R¹ is CH₂—A¹ and R² is CF₃CH₂—.

[0565] A group of compounds which is preferred within the XA Group ofcompounds, designated the XB Group, comprises those compounds wherein A¹is 2-pyridyl.

[0566] A compound which is preferred within the XB Group of compounds is8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione.

[0567] Another compound which is preferred within the XB group ofcompounds is the L-tartrate salt of8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione.

[0568] This invention also provides a process for preparing1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester comprising reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dionewith D-tartaric acid in a reaction 3inert solvent at 0° C. to about roomtemperature for about 5 minutes to about 48 hours.

[0569] This invention also provides a process for preparing2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride comprising

[0570] (a) reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dionewith D-tartaric acid in a reaction inert solvent to form1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester;

[0571] (b) reacting said1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester with3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid in the presence of a tertiary amine and 1-propanephosphonic acidcyclic anhydride in a reaction inert solvent to form(1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pydidin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester; and

[0572] (c) reacting said(1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester with concentrated hydrochlonrc acid in a reactioninert solvent to form2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

[0573] In general the compounds of Formula I can be made by processesknown in the chemical arts. Certain processes for the manufacture ofFormula I compounds are provided as further features of the inventionand are illustrated by the following reaction schemes.

[0574] In the above structural formulae and throughout the instantapplication, the following terms have the indicated meanings unlessexpressly stated otherwise:

[0575] The alkyl groups are intended to include those alkyl groups ofthe designated length in either a straight or branched configurationwhich may optionally contain double or triple bonds. Exemplary of suchalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl,propenyl, butadienyl, hexenyl and the like.

[0576] When the definition C₀-alkyl occurs in the definition, it means asingle covalent bond.

[0577] The alkoxy groups specified above are intended to include thosealkoxy groups of the designated length in either a straight or branchedconfiguration which may optionally contain double or triple bonds.Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxyand the like.

[0578] The term “halogen” or “halo” is intended to include the halogenatoms fluorine, chlorine, bromine and iodine.

[0579] The term “halogenated alkyl” is intended to include an alkylgroup as defined hereinabove substituted by one or more halogen atoms asdefined hereinabove.

[0580] The term “halogenated cycloalkyl” is intended to include acycloalkyl group substituted by one or more halogen atoms as definedhereinabove.

[0581] The term “aryl” is intended to include phenyl and naphthyl andaromatic 5- and 6-membered rings with 1 to 4 heteroatoms or fused 5-and/or 6-membered bicyclic rings with 1 to 4 heteroatoms of nitrogen,sulfur or oxygen. Examples of such heterocyclic aromatic rings arepyridine, thiophene (also known as thienyl), furan, benzothiophene,tetrazole, indole, N-methylindole, dihydroindole, indazole,N-formylindole, benzimidazole, thiazole, pyrimidine, and thiadiazole.

[0582] The expression “prodrug” refers to compounds that are drugprecursors which following administration, release the drug in vivo viasome chemical or physiological process (e.g., a prodrug on being broughtto the physiological pH is converted to the desired drug form).Exemplary prodrugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituents(e.g., when R¹ is —(CH₂)_(q)C(O)OX⁶ where X⁶ is hydrogen, or when R² orA¹ contains carboxylic acid) wherein the free hydrogen is replaced by(C₁-C₄)alkyl, (C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0583] Other exemplary prodrugs release an alcohol of Formula I whereinthe free hydrogen of the hydroxyl substituent (e.g., when R¹ containshydroxyl) is replaced by (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alka-noyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxy-carbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, (α-amino(C₁-C₄)alkanoyl, arylacetyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins,

[0584] —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

[0585] Prodrugs of this invention where a carboxyl group in a carboxylicacid of Formula I is replaced by an ester may be prepared by combiningthe carboxylic acid with the appropriate alkyl halide in the presence ofa base such as potassium carbonate in an inert solvent such as DMF at atemperature of about 0° C. to 100° C. for about 1 to about 24 hours.Alternatively, the acid is combined with the appropriate alcohol assolvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20° C. to 120° C.,preferably at reflux, for about 1 hour to about 24 hours. Another methodis the reaction of the acid in an inert solvent such as THF, withconcomitant removal of the water being produced by physical (e.g., DeanStark trap) or chemical (e.g., molecular sieves) means.

[0586] Prodrugs of this invention where an alcohol function has beenderivatized as an ether may be prepared by combining the alcohol withthe appropriate alkyl bromide or iodide in the presence of a base suchas potassium carbonate in an inert solvent such as DMF at a temperatureof about 0° C. to 100° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)_(m)ethane in the presence of a catalyticamount of acid in an inert solvent such as THF, according to a methoddescribed in U.S. Pat. No. 4,997,984. Alternatively, these compounds maybe prepared by the methods described by Hoffman et al. in J. Org. Chem.1994, 59, p. 3530.

[0587] Certain of the above defined terms may occur more than once inthe above formula and upon such occurrence each term shall be definedindependently of the other.

[0588] The compounds of the instant invention all have at least oneasymmetric center as noted by the asterisk in the structural Formula I.Additional asymmetric centers may be present on the molecule dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will produce two optical isomers and it is intendedthat all such optical isomers, as separated, pure or partially purifiedoptical isomers, racemic mixtures or diastereomeric mixtures thereof, beincluded within the scope of the instant invention. In the case of theasymmetric center represented by the asterisk, it has been found thatthe absolute stereochemistry of the more active and thus more preferredisomer is shown in Formula IA. This preferred absolute configurationalso applies to Formula I.

[0589] With the R⁴ substituent as hydrogen, the spatial configuration ofthe asymmetric center corresponds to that in a D-amino acid. In mostcases this is also designated an R-configuration although this will varyaccording to the values of R³ and R⁴ used in making R- orS-stereochemical assignments.

[0590] The instant compounds are generally isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric,malonic, methane sulfonic and the like. In addition, certain compoundscontaining an acidic function such as a carboxy can be isolated in theform of their inorganic salt in which the counter-ion can be selectedfrom sodium, potassium, lithium, calcium, magnesium and the like, aswell as from organic bases.

[0591] The pharmaceutically acceptable salts are formed by taking about1 equivalent of a compound of Formula I and contacting it with about 1equivalent of the appropriate corresponding acid of the salt which isdesired. Work-up and isolation of the resulting salt is well-known tothose of ordinary skill in the art.

[0592] The growth hormone releasing compounds of Formula I are useful invitro as unique tools for understanding how growth hormone secretion isregulated at the pituitary level. This includes use in the evaluation ofmany factors thought or known to influence growth hormone secretion suchas age, sex, nutritional factors, glucose, amino acids, fatty acids, aswell as fasting and non-fasting states. In addition, the compounds ofthis invention can be used in the evaluation of how other hormonesmodify growth hormone releasing activity. For example, it has alreadybeen established that somatostatin inhibits growth hormone release.

[0593] The compounds of Formula I can be administered to animals,including humans, to release growth hormone in vivo. The compounds areuseful for treating symptoms related to GH deficiency; stimulating pre-and post-natal growth or enhancing feed efficiency and improving carcassquality of animals raised for meat production; increasing milkproduction in dairy cattle; improving estrous synchronization inlivestock such as swine, beef and dairy cattle; improving bone or woundhealing and improving vital organ function in animals. The compounds ofthe present invention, by inducing endogenous GH secretion, will alterbody composition and modify other GH-dependent metabolic, immunologic ordevelopmental processes. For example, the compounds of the presentinvention can be given to chickens, turkeys, livestock animals (such assheep, pigs, horses, cattle, etc.) and companion animals (e.g., dogs).These compounds may also have utility in aquaculture to accelerategrowth and improve the percent lean meat. In addition, these compoundscan be administered to humans in vivo as a diagnostic tool to directlydetermine whether the pituitary is capable of releasing growth hormone.For example, the compounds of Formula I or a pharmaceutically acceptablesalt or prodrug thereof can be administered in vivo to children andserum samples taken before and after such administration can be assayedfor growth hormone. Comparison of the amounts of growth hormone in eachof these samples would be a means for directly determining the abilityof the patient's pituitary to release growth hormone.

[0594] Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I or a pharmaceutically acceptablesalt or prodrug thereof in association with a pharmaceuticallyacceptable carrier. Optionally, the pharmaceutical compositions canfurther comprise an anabolic agent in addition to at least one of thecompounds of Formula I or a pharmaceutically acceptable salt or prodrugthereof, or another compound which exhibits a different activity, e.g.,an antibiotic or coccidiostat (e.g., monensin) growth promotant or anagent to treat osteoporosis or with other pharmaceutically activematerials wherein the combination enhances efficacy and minimizes sideeffects.

[0595] Growth promoting and anabolic agents include, but are not limitedto, TRH, PTH, diethylstilbesterol, estrogens, β-agonists, theophylline,anabolic steroids, enkephalins, E series prostaglandins, compoundsdisclosed in U.S. Pat. No. 3,239,345, the disclosure of which is herebyincorporated by reference, e.g., zeranol; compounds disclosed in U.S.Pat. No. 4,036,979, the disclosure of which is hereby incorporated byreference, e.g., sulbenox; and peptides disclosed in U.S. Pat. No.4,411,890, the disclosure of which is hereby incorporated by reference.

[0596] The growth hormone secretagogues of this invention in combinationwith other growth hormone secretagogues such as the growth hormonereleasing peptides GHRP-6 and GHRP-1 as described in U.S. Pat. No.4,411,890, the disclosure of which is hereby incorporated by reference,and publications WO 89/07110, WO 89/07111 and B-HT920 as well ashexarelin and the newly discovered GHRP-2 as described in WO 93/04081 orgrowth hormone releasing hormone (GHRH, also designated GRF) and itsanalogs or growth hormone and its analogs or somatomedins includingIGF-1 and IGF-2 or alpha-2-adrenergic agonists such as clonidine,xylazine, detomidine and medetomidine or serotonin 5HTID agonists suchas sumitriptan or agents which inhibit somatostatin or its release suchas physostigmine and pyridostigmine, are useful for increasing theendogenous levels of GH in mammals. The combination of a GH secretagogueof this invention with GRF results in synergistic increases ofendogenous growth hormone.

[0597] As is well known to those skilled in the art, the known andpotential uses of growth hormone are varied and multitudinous [See“Human Growth Hormone”, Strobel and Thomas, Pharmacological Reviews, 46,pg. 1-34 (1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M.Degerblad et al., European Journal of Endocrinology, 1995, 133:pp.180-188; J. O. Jorgensen, European Journal of Endocrinology, 1994,130: pp. 224228; K. C. Copeland et al., Journal of ClinicalEndocrinology and Metabolism, Vol. 78 No. 5, pp. 1040-1047; J. A. Aloiet al., Journal of Clinical Endocrinology and Metabolism, Vol. 79 No. 4,pp. 943-949; F. Cordido et al., Metab. Clin. Exp., (1995), 44(6), pp.745-748; K. M. Fairhall et al., J. Endocrinol., (1995), 145(3), pp.417-426; R.M. Frieboes et al., Neuroendocrinology, (1995), 61(5), pp.584-589; and M. Llovera et al., Int. J. Cancer, (1995), 61(1), pp.138-141]. Thus, the administration of the compounds of this inventionfor purposes of stimulating the release of endogenous growth hormone canhave the same effects or uses as growth hormone itself. These varieduses of growth hormone may be summarized as follows: stimulating growthhormone release in elderly humans or companion animals especially dogs,cats, camels and horses; treating growth hormone deficient adult humansor other animals especially dogs, cats, camels and horses; preventingcatabolic side effects of glucocorticoids, treating osteoporosis,stimulating the immune system, accelerating wound healing, acceleratingbone fracture repair, treating growth retardation, treating congestiveheart failure as disclosed in PCT publications WO 95/28173 and WO95/28174 (an example of a method for assaying growth hormonesecretagogues for efficacy in treating congestive heart failure isdisclosed in R. Yang et al., Circulation, Vol. 92, No. 2, p.262, 1995),treating acute or chronic renal failure or insufficiency; treatingphysiological short stature including growth hormone deficient children,treating short stature associated with chronic illness, treatingobesity, treating growth retardation associated with Prader-Willisyndrome and Turners syndrome; accelerating the recovery and reducinghospitalization of bum patients or following major surgery such asgastrointestinal surgery; treating intrauterine growth retardation,skeletal dysplasia, hypercortisonism and Cushings syndrome; replacinggrowth hormone in stressed patients; treating osteochondrodysplasias,Noonans syndrome, sleep disorders, Alzheimers disease, delayed woundhealing, and psychosocial deprivation; treating pulmonary dysfunctionand ventilator dependency; attenuating protein catabolic response aftera major operation; treating malabsorption syndromes, reducing cachexiaand protein loss due to chronic illness such as cancer or AIDS;accelerating weight gain and protein accretion in patients on TPN (totalparenteral nutrition); treating hyperinsulinemia includingnesidioblastosis; adjuvant treatment for ovulation induction and toprevent and treat gastric and duodenal ulcers; stimulating thymicdevelopment and preventing age-related decline of thymic function;adjunctive therapy for patients on chronic hemodialysis; treatingimmunosuppressed patients and enhancing antibody response followingvaccination; improving muscle strength, increasing muscle mass,mobility, maintenance of skin thickness, metabolic homeostasis, renalhemeostasis in the frail elderly; stimulating osteoblasts, boneremodeling, and cartilage growth; treating neurological diseases such asperipheral and drug induced neuropathy, Guillian-Barre Syndrome,amyotrophic lateral sclerosis, multiple sclerosis, cerebrovascularaccidents and demyelinating diseases; and stimulating wool growth insheep.

[0598] Uses of GH in farm animals raised for meat production such aschickens, turkeys, sheep, pigs and cattle include stimulation of pre-and post- natal growth, enhanced feed efficiency in animals raised formeat production, improved carcass quality (increased muscle to fatratio) (Campbell, R. G. et al., (1989), J. Anim. Sci. 67, 1265; Dave, D.J., Bane, D. P., (1990), The Compendium Food Anual, Vol. 12(1), 117;Holden, P. J., (1990), Agri-Practice, 11(3), 25; Claus, R., Weiber, U.,(1994), Livestock Production Science, 37, 245; Roeder, R. et al.,(1994), Growth Regulation, 4, 101); increased milk production in dairycattle (McBride, B. W. et al., (1988), Research and Development inAgriculture 5(1), 1; McDowell, G. H. et al., (1988), Aust. J. Biol.Sci., 41, 279); improved body composition; modification of otherGH-dependent metabolic (Claus, R. and Weiber, U., (1994), LivestockProduction Science, 37, 245) and immunologic functions such as enhancingantibody response following vaccination or improved developmentalprocesses; and may have utility in aquaculture to accelerate growth andimprove the protein-to-fat ratio in fish.

[0599] Preferred uses in companion animals include stimulatingendogenous growth hormone release in companion animals such as dogs,cats and horses; treating disorders of aging (Detenbeck, L. C., Jowsey,J., Clinical Orthopedics and Related Research, July-August 1969, No. 65,pp. 76-80); stimulating thymic development and preventing age-relateddecline of thymic function (Goff, B. L. et al., Clinical andExperimental Immunology, 1987, 68:3, pp. 580-587; Morrison, W. B. etal., Am. J. Vet. Res., Jan. 1990, 51:1, pp. 65-70; Roth, J. A. et al.,Am. J. Vet. Res., 1984, Vol. 45, pp. 1151-1155); preventing age-relateddecline of thymic function; preventing age-related decline in cognition;accelerating wound healing (Jacks, T. et al., Vet. Surg. 1996, 25, (5),430); accelerating bone fracture repair (Pandey, S. K, Udupa, K. N.,Indian J. Vet. Surg. 1 (2): 73-78, July 1980); stimulating osteoblasts,bone remodelling and cartilage growth (Harris, W. H. et al., Calc. Tiss.Res., 10, 1972, pp. 1-13; Heaney, R. P. et al., Calc. Tiss. Res. 10,1972, pp. 14-22; Mankin. H. J. et al., J. of Bone and Joint Surgery,Vol. 60-A, #8, December 1978, pp. 1071-1075); attenuating proteincatabolic response after major surgery, accelerating recovery from buminjuries and major surgeries such as gastrointestinal surgery;stimulating the immune system and enhancing antibody response followingvaccination; treating congestive heart failure, treating acute orchronic renal failure or insufficiency, treating obesity; treatinggrowth retardation, skeletal dysplasia and osteochondrodysplasias;preventing catabolic side effects of glucocorticoids; treating Cushing'ssyndrome; treating malabsorption syndromes, reducing cachexia andprotein loss due to chronic illness such as cancer; accelerating weightgain and protein accretion in animals receiving total parenteralnutrition; providing adjuvant treatment for ovulation induction and toprevent gastrointestinal ulcers; improving muscle mass, strength andmobility; maintenance of skin thickness, and improving vital organfunction and metabolic homeostasis.

[0600] The growth hormone secretagogues of this invention, compounds ofFormula I, or a pharmaceutically acceptable salt or prodrug thereof incombination with an alpha-2 adrenergic agonist are useful in promotingGH secretion in humans and other animals (See Cella, S. G. et al., ActaEndocrinologica (Copenh.) 1989, 121, pp. 177-184). As such, acombination of a compound of Formula I or a pharmaceutically acceptablesalt or prodrug thereof and an alpha-2 adrenergic agonist is useful inthe treatment or prevention of frailty associated with aging, congestiveheart failure and obesity which comprises administering to a human oranother animal, especially dogs, cats and horses, in need of suchtreatment a combination of an alpha-2 adrenergic agonist and a compoundof Formula I or a pharmaceutically acceptable salt or prodrug thereof,defined above. Preferred alpha-2 adrenergic agonists include clonidine,which is disclosed in U.S. Pat. No. 3,202,660 the disclosure of which ishereby incorporated by reference, xylazine, which is disclosed in U.S.Pat. No. 3,235,550 the disclosure of which is hereby incorporated byreference and medetomidine, which is disclosed in U.S. Pat. No.4,544,664 the disclosure of which is hereby incorporated by reference.In another aspect, this invention provides methods for accelerating bonefracture repair and wound healing, attenuating protein catabolicresponse after a major operation, and reducing cachexia and protein lossdue to chronic illness, which comprise administering to a human oranother animal, especially dogs, cats and horses in need of suchtreatment a combination of an alpha-2 adrenergic agonist such asclonidine, xylazine or medetomidine and a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof. It has been shownthat alpha-2 adrenergic agonists cause release of endogenous growthhormone in human and canine subjects (Celia et al., Life Sciences(1984), 34:447-454; Hampshire J, Altszuler N., American Journal ofVeterinary Research (1981), 42:6, 1073-1076; Valcavi et al., ClinicalEndocrinology (1988), 29:309-316; Morrison et al., American Journal ofVeterinary Research (1990), 51:1, 65-70;), and that theco-administration of an alpha-2 adrenergic agonist with growthhormone-releasing factor restores defective growth hormone secretion inaged dogs (Arce et al., Brain Research (1990), 537:359-362; Cella et.al., Neuroendocrinology (1993), 57:432-438).

[0601] This invention also relates to a method of treating insulinresistant conditions such as Non-insulin Dependent Diabetes Mellitus(NIDDM) and reduced glycemic control associated with obesity and agingin a mammal in need thereof which comprises administering to said mammalan effective amount of a compound of the Formula I or a pharmaceuticallyacceptable salt or prodrug thereof.

[0602] This invention is directed to the use of growth hormonesecretagogues specifically growth hormone releasing peptides (GHRP) orGHRP mimetics of Formula I or a pharmaceutically acceptable salt orprodrug thereof to improve glycemic control. Agents that increase growthhormone (GH) levels would not be expected to have this effect since itis widely recognized that GH is diabetogenic in animals and in humans.In acromegalics, glucose utilization and suppression of hepatic glucoseproduction are impaired (see Hansen, I., et al., Am J Physiol, 250:E269(1986)). In this disease of GH excess, impaired glucose handling andhyperinsulinemia have been reversed by pituitary surgery or chemotherapywhich reduced GH levels (see Levin S. R., et al., Am J Med, 57:526(1974), Feek, C. M., et al., J Clin Endocrinol 22:532 (1981)).Furthermore, administration of GH to older subjects causedhyperglycemia, glucose intolerance and hyperinsulinemia in numerousstudies (see Aloia, J. F., et al., J Clin Endocrinol Metab, 43:992(1976); Binnerts et al., J Clin Endocrinol Metab, 67:1312 (1988);Marcus, R., et al., J Clin Endocrinol Metab, 70:519 (1990)). Therefore,GH therapy is contra-indicated for individuals with diabetes or those atrisk for diabetes.

[0603] It will be known to those skilled in the art that there arenumerous compounds now being used in an effort to treat the diseases ortherapeutic indications enumerated above. Combinations of thesetherapeutic agents, some of which have also been mentioned above, withgrowth promotant, exhibit anabolic and desirable properties of thesevarious therapeutic agents. In these combinations, the therapeuticagents and the growth hormone secretagogues of this invention may beindependently and sequentially administered in any order orco-administered in dose ranges from one one-hundredth to one times thedose levels which are effective when these compounds and secretagoguesare used singly. Combined therapy to inhibit bone resorption, preventosteoporosis, reduce skeletal fracture, enhance the healing of bonefractures, stimulate bone formation and increase bone mineral densitycan be effectuated by combinations of bisphosphonates and the growthhormone secretagogues of this invention. See PCT publication WO 95/11029for a discussion of combination therapy using bisphosphonates and GHsecretagogues. The use of bisphosphonates for these utilities has beenreviewed, for example, by Hamdy, N. A. T., Role of Bisphosphonates inMetabolic Bone Diseases, Trends in Endocrinol. Metab., 1993, 4, pages19-25. Bisphosphonates with these utilities include but are not limitedto alendronate, tiludronate, dimethyl-APD, risedronate, etidronate,YM-175, clodronate, pamidronate, and BM-210995 (ibandronate). Accordingto their potency, oral daily dosage levels of the bisphosphonate ofbetween 0.1 mg/kg and 5 g/kg of body weight and daily dosage levels ofthe growth hormone secretagogues of this invention of between 0.01 mg/kgto 20 mg/kg of body weight are administered to patients to obtaineffective treatment of osteoporosis.

[0604] The compounds of this invention may be combined with a mammalianestrogen agonist/antagonist. Any estrogen agonist/antagonist may be usedas the second compound of this invention. The term estrogenagonist/antagonist refers to compounds which bind with the estrogenreceptor, inhibit bone turnover and prevent bone loss. In particular,estrogen agonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, andmimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art according to standard assaysincluding estrogen receptor binding assays, standard bonehistomorphometric and densitometer methods (see Eriksen E. F. et al.,Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, other estrogenagonists/antagonists will be known to those skilled in the art. Apreferred estrogen agonist/antagonist is droloxifene: (phenol,3-[1-[4[2-(dimethylamino)ethoxy]-phenyl]-2-phenyl-1-butenyl]-, (E)-) andassociated compounds which are disclosed in U.S. Pat. No. 5,047,431, thedisclosure of which is hereby incorporated by reference.

[0605] Another preferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl,(Z)-2,2-hydroxy-1,2,3-propanetricarboxylate (1:1)) and associatedcompounds which are disclosed in U.S. Pat. No. 4,536,516, the disclosureof which is hereby incorporated by reference. Another related compoundis 4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660,the disclosure of which is hereby incorporated by reference.

[0606] Another preferred estrogen agonistlantagonist is raloxifene:(methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4[2-(1-piperidinyl)ethoxy]phenyl]-hydrochloride)and associated compounds which are disclosed in U.S. Pat. No. 4,418,068,the disclosure of which is hereby incorporated by reference.

[0607] Another preferred estrogen agonistlantagonist is idoxifene:Pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-Butenyl]phenoxy]ethyl]and associated compounds which are disclosed in U.S. Pat. No. 4,839,155,the disclosure of which is hereby incorporated by reference.

[0608] Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412 the disclosure ofwhich is hereby incorporated by reference. Especially preferredcompounds which are described therein are:

[0609]cis-6-(4-fluoro-phenyl)-5-[4(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0610](−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0611]cis6-phenyl-5[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0612]cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

[0613]1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0614]cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

[0615]1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

[0616] Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814, the disclosure of which is hereby incorporated by reference.U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

[0617] The following paragraphs provide preferred dosage ranges forvarious anti-resorptive agents.

[0618] The amount of the anti-resorptive agent to be used is determinedby its activity as a bone loss inhibiting agent. This activity isdetermined by means of an individual compound's pharmacokinetics and itsminimal maximal effective dose in inhibition of bone loss using aprotocol such as those referenced above.

[0619] In general an effective dosage for the activities of thisinvention, for example the treatment of osteoporosis, for the estrogenagonists/antagonists (when used in combination with a compound ofFormula I or a pharmaceutically acceptable salt or prodrug thereof ofthis invention) is in the range of 0.01 to 200 mg/kg/day, preferably 0.5to 100 mg/kg/day.

[0620] In particular, an effective dosage for droloxifene is in therange of 0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

[0621] In particular, an effective dosage for raloxifene is in the rangeof 0.1 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

[0622] In particular, an effective dosage for tamoxifen is in the rangeof 0.1to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

[0623] In particular, an effective dosage for

[0624]cis-6-(4fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0625](−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0626]cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0627] cis-1 -[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

[0628] 1 -(4!-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0629]cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or

[0630]1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineis in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10mg/kg/day.

[0631] In particular, an effective dosage for 4-hydroxy tamoxifen is inthe range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

[0632] Assay for stimulation of GH release from rat pituicytes

[0633] Compounds that have the ability to stimulate GH secretion fromcultured rat pituitary cells are identified using the followingprotocol. This test is also useful for comparison to standards todetermine dosage levels. Cells are isolated from pituitaries of 6-weekold male Wistar rats. Following decapitation, the anterior pituitarylobes are removed into cold, sterile Hank's balanced salt solutionwithout calcium or magnesium (HBSS). Tissues are finely minced, thensubjected to two cycles of mechanically assisted enzymatic dispersionusing 10 U/mL bacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis,Mo.) in HBSS. The tissue-enzyme mixture is stirred in a spinner flask at30 rpm in a 5% CO₂ atmosphere at about 37° C. for about 30 min., withmanual trituration after about 15 min. and about 30 min. using a 10-mLpipet. This mixture is centrifuged at 200×g for about 5 min. Horse serum(35% final concentration) is added to the supematant to neutralizeexcess protease. The pellet is resuspended in fresh protease (10 U/mL),stirred for about 30 min. more under the previous conditions, andmanually triturated, ultimately through a 23-gauge needle. Again, horseserum (35% final concentration) is added, then the cells from bothdigests are combined, pelleted (200×g for about 15 min.), resuspended inculture medium (Dulbecco's Modified Eagle Medium (D-MEM) supplementedwith 4.5 g/L glucose, 10% horse serum, 2.5% fetal bovine serum, 1%non-essential amino acids, 100 UlmL nystatin and 50 mg/mL gentamycinsulfate, Gibco, Grand Island, N.Y.) and counted. Cells are plated at6.0-6.5×10⁴ cells per cm² in 48-well Costar™ (Cambridge, Mass.) dishesand cultured for 3-4 days in culture medium.

[0634] Just prior to GH secretion assay, culture wells are rinsed twicewith release medium, then equilibrated for about 30 minutes in releasemedium (D-MEM buffered with 25 mM Hepes, pH 7.4 and containing 0.5%bovine serum albumin at 37° C.). Test compounds are dissolved in DMSO,then diluted into pre-warmed release medium. Assays are run inquadruplicate. The assay is initiated by adding 0.5 mL of release medium(with vehicle or test compound) to each culture well. Incubation iscarried out at about 37° C. for about 15 minutes, then terminated byremoval of the release medium, which is centrifuged at 2000×g for about15 minutes to remove cellular material. Rat growth hormoneconcentrations in the supematants are determined by a standardradioimmunoassay protocol described below.

[0635] Measurement of rat growth hormone

[0636] Rat growth hormone concentrations were determined by doubleantibody radioimmunoassay using a rat growth hormone referencepreparation (NIDDK-rGH-RP-2) and rat growth hormone antiserum raised inmonkey (NlDDK-anti-rGH-S5) obtained from Dr. A. Parlow (Harbor-UCLAMedical Center, Torrence, Calif.). Additional rat growth hormone (1.5U/mg, #G2414, Scripps Labs, San Diego, Calif.) is iodinated to aspecific activity of approximately 30 μCi/μg by the chloramine T methodfor use as tracer. Immune complexes are obtained by adding goatantiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethyleneglycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery isaccomplished by centrifugation. This assay has a working range of0.08-2.5 μg rat growth hormone per tube above basal levels.

[0637] Assay for Exogenously-Stimulated Growth Hormone Release in theRat after Intravenous Administration of Test Compounds

[0638] Twenty-one day old female Sprague-Dawley rats (Charles RiverLaboratory, Wilmington, Mass.) are allowed to acclimate to localvivarium conditions (24° C., 12 hr light, 12 hr dark cycle) forapproximately 1 week before compound testing. All rats are allowedaccess to water and a pelleted commercial diet (Agway Country Food,Syracuse N.Y.) ad libitum. The experiments are conducted in accordancewith the NIH Guide for the Care and Use of Laboratory Animals.

[0639] On the day of the experiment, test compounds are dissolved invehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serumalbumin in saline. Each test is conducted in three rats. Rats areweighed and anesthetized via intraperitonreal injection of sodiumpentobarbital (Nembutol®, 50 mg/kg body weight). Fourteen minutes afteranesthetic administration, a blood sample is taken by nicking the tip ofthe tail and allowing the blood to drip into a microcentrifuge tube(baseline blood sample, approximately 100 μl). Fifteen minutes afteranesthetic administration, test compound is delivered by intravenousinjection into the tail vein, with a total injection volume of 1 mL/kgbody weight. Additional blood samples are taken from the tail at 5, 10and 15 minutes after compound administration. Blood samples are kept onice until serum separation by centrifugation (1430xg for 10 minutes at10° C.). Serum is stored at −80° C. until serum growth hormonedetermination by radioimmunoassay as described above.

[0640] Assessment of Exogenously-Stimulated Growth Hormone Release inthe Dog after Oral Administration

[0641] On the day of dosing, the test compound is weighed out for theappropriate dose and dissolved in water. Doses are delivered at a volumeof 0.5-3 mL/kg by gavage to 2-4 dogs for each dosing regimen. Bloodsamples (5 mL) are collected from the jugular vein by direct venapuncture pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24hours post dose using 5 mL vacutainers containing lithium heparin. Theprepared plasma is stored at −20° C. until analysis.

[0642] Measurement of Canine Growth Hormone

[0643] Canine growth hormone concentrations are determined by a standardradioimmunoassay protocol using canine growth hormone (antigen foriodination and reference preparation AFP-1983B) and canine growthhormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A.Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer isproduced by chloramine T-iodination of canine growth hormone to aspecific activity of 20-40 μCi/μg. Immune complexes are obtained byadding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation. This assay has a workingrange of 0.08-2.5 μg canine GH/tube.

[0644] Assessment of Canine Growth Hormone and Insulin-Like GrowthFactor-1 Levels in the dog after chronic oral administration

[0645] The dogs receive test compound daily for either 7 or 14 days.Each day of dosing, the test compound is weighed out for the appropriatedose and dissolved in water. Doses are delivered at a volume of 0.5-3ml/kg by gavage to 5 dogs for each dosing regimen. Blood samples arecollected at days 0, 3, 7, 10 and 14. Blood samples (5 ml) are obtainedby direct venipuncture of the jugular vein at pre-dose, 0.17, 0.33, 0.5,0.754, 1, 2, 3, 6, 8, 12 and 24 hours post administration on days 0, 7and 14 using 5 ml vacutainers containing lithium heparin. In addition,blood is drawn pre-dose and 8 hours on days 3 and 10. The preparedplasma is stored at −20° C. until analysis.

[0646] Female Rat Study

[0647] This study evaluates the effect of chronic treatment with a GHRPmimetic on weight, body composition and non-fasting plasmaconcentrations of glucose, insulin, lactate and lipids inestrogen-deficient and estrogen-replete female rats. Acuteresponsiveness of serum GH levels to i.v. administration of the GHreleasing agent was assessed on the last day of dosing. Body weight wasmonitored weekly throughout the treatment period; additionally, bodycomposition and plasma levels of glucose, insulin, lactate, cholesteroland triglycerides were assessed at the end of treatment.

[0648] Virgin female Sprague-Dawley rats were obtained from CharlesRiver Laboratories (Wilmington, Mass.) and underwent bilateralovariectomy (Ovx) or sham-surgery (Sham) at approximately 12 weeks ofage. For sham surgeries, ovaries were exteriorized and replaced into theabdominal cavity. Following surgery the rats were housed individually in20 cm×32 cm×20 cm cages under standard vivarium conditions (about 24° C.with about 12 hours light/12 hours dark cycle). All rats were allowedfree access to water and a pelleted commercial diet (Agway ProLab 3000,Agway Country Food, Inc., Syracuse, N.Y.). The experiment was conductedin accordance with NIH Guidelines for the Care and Use of LaboratoryAnimals.

[0649] Approximately seven months post-surgery, Sham and Ovx rats wereweighed and randomly assigned to groups. Rats were dosed daily by oralgavage with 1 mL of either vehicle (1% ethanol in distilled-deionizedwater), 0.5 mg/kg or 5 mg/kg of a growth hormone releasing agent for 90days. Rats were weighed at weekly intervals throughout the study.Twenty-four hours after the last oral dose, the acute response of serumgrowth hormone (GH) to test agent was assessed by the followingprocedure. Rats were anesthetized with sodium pentobarbital 50 mg/kg.Anesthetized rats were weighed and a baseline blood sample (˜100 pl) wascollected from the tail vein. Test agent (growth hormone releasing agentor vehicle) was then administered intravenously via the tail vein in 1mL. Approximately ten minutes after injection, a second 100 μl bloodsample was collected from the tail. Blood was allowed to clot at about4° C., then centrifuged at 2000×g for about 10 minutes. Serum was storedat about −70° C. Serum growth hormone concentrations were determined byradioimmunoassay as previously described. Following this procedure, eachanesthetized rat underwent whole body scanning by dual-energy X-rayabsorptiometry (DEXA, Hologic QDR 1000/W, Waltham Mass.). A final bloodsample was collected by cardiac puncture into heparinized tubes. Plasmawas separated by centrifugation and stored frozen as described above.

[0650] Plasma insulin is determined by radioimmunoassay using a kit fromBinax Corp. (Portland, Me.). The interassay coefficient of variation is≦10%. Plasma triglycerides, total cholesterol, glucose and lactatelevels are measured using Abbott VP™ and VP Super System® Autoanalyzer(Abbott Laboratories, Irving, Tex.), using the A-Gent™ Triglycerides,Cholesterol and Glucose Test reagent systems, and a lactate kit fromSigma, respectively. The plasma insulin, triglycerides, totalcholesterol and lactate lowering activity of a growth hormone releasingpeptide (GHRP) or GHRP mimetic such as a compound of Formula I, aredetermined by statistical analysis (unpaired t-test) with thevehicle-treated control group.

[0651] The compounds of this invention can be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous orsubcutaneous injection, or implant), nasal, vaginal, rectal, sublingual,or topical routes of administration and can be formulated withpharmaceutically acceptable carriers to provide dosage forms appropriatefor each route of administration.

[0652] Solid dosage forms for oral administration include capsules,tablets, pills, powders and granules and for companion animals the soliddosage forms include an admixture with food and chewable forms. In suchsolid dosage forms, the active compound is admixed with at least oneinert pharmaceutically acceptable carrier such as sucrose, lactose, orstarch. Such dosage forms can also comprise, as is normal practice,additional substances other than such inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings. In the case ofchewable forms, the dosage form may comprise flavoring agents andperfuming agents.

[0653] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,the elixirs containing inert diluents commonly used in the art, such aswater. Besides such inert diluents, compositions can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,and sweetening, flavoring and perfuming agents.

[0654] Preparations according to this invention for parenteraladministration include sterile aqueous or non-aqueous solutions,suspensions, or emulsions. Examples of non-aqueous solvents or vehiclesare propylene glycol, polyethylene glycol, vegetable oils, such as oliveoil and corn oil, gelatin, and injectable organic esters such as ethyloleate. Such dosage forms may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized by,for example, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

[0655] Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

[0656] Compositions for nasal or sublingual administration are alsoprepared with standard excipients well known in the art.

[0657] The dosage of active ingredient in the compositions of thisinvention may be varied; however, it is necessary that the amount of theactive ingredient be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment.Generally, dosage levels of between 0.0001 to 100 mg/kg of body weightdaily are administered to humans and other animals, e.g., mammals, toobtain effective release of growth hormone.

[0658] A preferred dosage range in humans is 0.01 to 5.0 mg/kg of bodyweight daily which can be administered as a single dose or divided intomultiple doses.

[0659] A preferred dosage range in animals other than humans is 0.01 to10.0 mg/kg of body weight daily which can be administered as a singledose or divided into multiple doses. A more preferred dosage range inanimals other than humans is 0.1 to 5 mg/kg of body weight daily whichcan be administered as a single dose or divided into multiple doses.

[0660] Throughout this disclosure the following abbreviations are usedwith the following meanings:

[0661] BOC t-Butyloxycarbonyl

[0662] Bz Benzyl

[0663] BOP Benzotriazol-1-yloxy tris(dimethylamino) phosphoniumhexafluorophosphate

[0664] CBZ Benzyloxycarbonyl

[0665] CDI N,N′-Carbonyldiimidazole

[0666] DCC Dicyclohexylcarbodiimide

[0667] DEC 1,2-Diethylaminoethyl chloride hydrochloride

[0668] DMAP 4-Dimethylaminopyridine

[0669] DMF Dimethylformamide

[0670] DPPA Diphenylphosphoryl azide

[0671] EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0672] EtOAc Ethyl acetate

[0673] Hex Hexane

[0674] HOAT 1-Hydroxy-7-azabenzotriazole

[0675] HOBT Hydroxybenzotriazole hydrate

[0676] HPLC High pressure liquid chromatography

[0677] Hz Hertz

[0678] KHMDS Potassium Bis(trmethylsilyl)amide

[0679] LHMDS Lithium Bis(trimethylsilyl)amide

[0680] MHz Megahertz

[0681] MS Mass Spectrum

[0682] NaHMDS Sodium Bis(trimethylsilyl)amide

[0683] NMR Nuclear Magnetic Resonance

[0684] PPM 1-Propanephosphonic acid cyclic anhydride

[0685] PTH Parathyroid hormone

[0686] TFA Trifluoroacetic acid

[0687] THF Tetrahydrofuran

[0688] TLC Thin layer chromatography

[0689] TRH Thyrotropin releasing hormone

[0690] The preparation of the compounds of Formula I of the presentinvention can be carried out in sequential or convergent syntheticroutes. Syntheses detailing the preparation of the compounds of FormulaI in a sequential manner are presented in the following reactionschemes.

[0691] Many protected amino acid derivatives are commercially available,where the protecting groups, Prt, Prt′ or Prt″, are, for example, BOC,CBZ, FMOC, benzyl or ethoxycarbonyl groups. Other protected amino acidderivatives can be prepared by literature methods well-known to oneskilled in the art. Some substituted piperazines and piperidines arecommercially available, and many other piperazines and 4-substitutedpiperidines are known in the literature. Various heterocyclicsubstituted piperidines and piperazines can be prepared followingliterature methods using derivatized heterocyclic intermediates.Alternatively, the heterocyclic rings of such compounds can bederivatized by standard means, such as coupling with CDl, hydrogenationof aromatic heterocycles, etc. as is well-known to those skilled in theart.

[0692] Many of the schemes illustrated below describe compounds whichcontain protecting groups Prt, Prt′ or Prt″, which can be any suitableprotecting group known to those skilled in the art. Benzyloxycarbonylgroups can be removed by a number of methods including, catalytichydrogenation with hydrogen in the presence of a palladium or platinumcatalyst in a protic solvent such as methanol. Preferred catalysts arepalladium hydroxide on carbon or palladium on carbon. Hydrogen pressuresfrom 1-1000 psi can be employed; pressures from 10 to 70 psi arepreferred. Alternatively, the benzyloxycarbonyl group can be removed bytransfer hydrogenation.

[0693] Removal of BOC protecting groups can be carried out using astrong acid such as trifluoroacetic acid or hydrochloric acid with orwithout the presence of a cosolvent such as dichloromethane or methanolat a temperature of about −30° to 70° C., preferably about −50° to about35° C.

[0694] Benzyl groups on amines can be removed by a number of methodsincluding catalytic hydrogenation with hydrogen in the presence of apalladium catalyst in a protic solvbnt such as methanol. Hydrogenpressures from 1-1000 psi can be employed; pressures from 10 to 70 psiare preferred. The addition and removal of these and other protectinggroups are discussed in detail by T. Greene in Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1981.

[0695] The variables shown in the following schemes are as described forcompounds of Formula I, above, unless otherwise indicated.

[0696] As illustrated in Scheme 1, coupling of a heterocyclic amine (HETat the NH) of formula 1-2, as defined for Formula I, With a protectedamino acid of formula 1-1, where Prt is a suitable protecting group, isconveniently carried out in an inert solvent such as dichloromethane orDMF by a coupling reagent such as EDC, DCC or DEC in the presence ofHOBT or HOAT. In the case where amine 1-2 is present as thehydrochloride salt, it is preferable to add one equivalent of a suitablebase such as triethylamine to the reaction mixture. Alternatively, thecoupling can be effected with a coupling reagent such as BOP in an inertsolvent such as methanol or with PPMA in a solvent like ethyl acetate.Such coupling reactions are generally conducted at temperatures of about−30° to about 80° C., preferably 0° to about 25° C. For a discussion ofother conditions used for coupling peptides see Houben-Weyl, Vol. XV,part II, E. Wunsch, Ed., George Theime Vedag, 1974, Stuttgart.Separation of unwanted side products and purification of intermediatesis achieved by chromatography on silica gel, employing flashchromatography (W. C. Still, M. Kahn and A. Mitra, J. Org. Chem. 43 29231978), by crystallization, or by trituration. Transformation of 1-3 intoan intermediate of formula 1-4 can be carried out by removal of theprotecting group Prt as described above.

[0697] As illustrated in Scheme 2, coupling of a heterocyclic amine offormula 1-2, as defined in claim 1, with an amino acid of formula 2-1,where R⁷ and R⁸ are not hydrogen, is conveniently carried out in amanner similar to that described in Scheme 1.

[0698] As illustrated in Scheme 3, an intermediate ether of formula 3-2can be prepared by treating an amino acid of formula 3-1, where Prt is asuitable protecting group, with a base such as potassium carbonate orsodium hydride followed by an alkyl halide, benzyl halide, tosylate ormesylate such as benzylbromide in a suitable solvent such as DMF or THF.Deprotection of the amine transforms 3-2 into 3-3. Altematively, manyamino acids of formula 3-3 are commercially available. R is a groupdefined for R³ in Formula I, above.

[0699] As illustrated in Scheme 4, intermediates of formula 4-2 can beprepared by treating an acid of formula 4-1 with hydroxysuccinimide inthe presence of a coupling agent such as EDC in an inert solvent such asmethylene chloride. Treating 4-2 with an amino acid of formula 4-3 in asolvent such as DMF in the presence of a base such asduisopropylethylamine produces compounds of formula 1-1.

[0700] As illustrated in Scheme 5, dipeptides of formula 2-1, where R⁷and R⁸ are not hydrogen, is conveniently synthesized by the proceduresdescribed in Scheme 4.

[0701] Intermediate esters of formula 62, where Prt and Prt′ areprotecting groups, preferrably Prt′ is a carbamate protecting group suchas CBZ, can be prepared by treating an acid of formula 6-1 with a basesuch as potassium carbonate followed by an alkyl halide such asiodomethane in a suitable solvent such as DMF. Alternatively, an esterof formula 6-2 can be prepared by reacting an acid of formula 6-1 withdiazomethane. For the preparation of compound 6-2 see Bigge, C. F. etal., Tet. Lett., 1989, 30, 5193-5196. Intermediate 6-4 is generated byalkylating ester 6-2 with a reagent such as an alkyl halide, tosylate ormesylate with a base such as NaHMDS in a suitable solvent system such asDMFITHF at a temperature of about −78° C.

[0702] Intermediate carbamates of formula 6-5 can be prepared byreacting an intermediate of formula 6-4 with a hydride such as sodiumborohydride or superhydride. Transformation of intermediate 6-5 to 6-6can be achieved by removal of the protecting group Prt as describedabove.

[0703] Transformation of intermediate 6-4 to 7-1 can be achieved byremoval of the protecting group Prt′ as described above. Intermediateureas of formula 7-5 can be prepared by reacting an intermediate offormula 7-1 with either an acyl imidizolide of formula 7-2, anisocyanate of formula 7-3, or phosgene (or other phosgene equivalent)followed by an amine of formula 7-4 in the presence of a suitable basesuch as triethylamine. When R¹ is —CH₂-pyridyl it is preferred to use anisocyanate or acyl imidizolide. Transformation of 7-5 to 7-6 can beachieved by removal of the protecting group Prt as described above.

[0704] An intermediate benzylamine of formula 8-1 can be prepared bytreating an amine of formula 7-1 with a base such asdiisopropylethylamine followed by a benzyl halide such as benzyl bromidein a suitable solvent such as acetonitrile. Alternatively, 8-1 can beprepared by treating 7-1 with benzaldehyde and a suitable reducing agentsuch as NaCNBH₃ or Na(OAc)₃BH in a suitable solvent such as methanol ordichloromethane. An alcohol of the formula 8-2 can be prepared byreducing an intermediate of the formula 8-1 with a reducing agent suchas superhydride in a suitable solvent such as THF. An alcohol of theformula 8-2 can be oxidized to an aldehyde of the formula 8-3 with anoxidizing agent such as oxalyl chloride/DMSO in a suitable solvent suchas dichloromethane at a temperature of about −78° C., with the lateraddition of a base such as triethylamine to neutralize the reactionmixture (Swem-type oxidation, see Mancuso, A. J., Swem, D., Syhthesis,1981, pp. 165-185). Compounds of formula 8-5 can be prepared by treatingan aldehyde of formula 8-3 with an amine of formula 84 in the presenceof a suitable reducing agent which include alkali metal borohydrides andcyanoborohydrides. The preferred reducing agent is sodiumcyanoborohydride. Sodium borohydride and sodium triacetoxyborohydridemay also be used. For a general review of reductive aminations see R. F.Borch, Aldrichimica Acta, 8, 3-10 (1975). Removal of the benzyl group togive 8-6 can be accomplished by a number of reductive methods includinghydrogenation in the presence of platinum or palladium catalyst in aprotic solvent such as methanol. Cyclization of a diamine of formula 8-6with CDl or other phosgene equivalents generates a compound of formula8-7. Removal of the protecting group, as described above, transforms 8-7into 8-8.

[0705] As illustrated in Scheme 9, an intermediate hydantoin of formula9-4 can be prepared in three steps. An ester of formula 9-1, prepared bycleavage of Prt′ from 6-2, can be acylated with an acyl imidizolide offormula 7-2, an isocyanate of formula 7-3, or phosgene (or otherphosgene equivalent) followed by an amine of formula 7-4 in the presenceof a suitable base such as triethylamine. Transformation of 9-3 to 9-4can be accomplished by removal of the protecting group Prt as describedabove.

[0706] Intermediates of formula 10-1 can be prepared by treating acompound of formula 7-1 with an acyl chloride or other activatedcarboxylic acid derivative and a suitable base, such as TEA orN,N-diisopropylethylamine. Cyclization of a compound of formula 10-1occurs upon treating 10-1 with a strong base such as LHMDS at a suitabletemperature, about −78° C. to 40° C., to produce an intermediate offormula 10-2. When R⁹ and/or R¹⁰ is H, 10-2 may be alkylated with areagent such as methyl iodide in the presence of a base like NaH to give10-2 where R⁹ and R¹⁰ are not H. Removal of the protecting group, asdescribed above, transforms 10-2 to 10-3.

[0707] Intermediate α,β-unsaturated esters of formula 11-3 (R is analkyl group) can be prepared by olefinating 11-1 with a reagent such asthe anion generated upon treating trimethylphosphonoacetate with astrong base such as potassium tert-butoxide in a suitable solvent suchas THF. Catalytic hydrogenation, such as with Pd on carbon in thepresence of hydrogen, preferably at 1-4 atmospheres, in a suitablesolvent, such as ethyl acetate or methanol, reduces the double bond of11-3 to produce 11-4. Selective hydrolysis of the less hindered estergroup in 11-4 can be performed with a base such as an alkali metalhydroxide in an appropriate solvent, such as a mixture of water,methanol, and/or dioxane. A carboxylic acid of formula 11-5, thusproduced can be transformed to 11-6 by converting 11-5 to an acyl azide,such as with DPPA and TEA in benzene, followed by rearrangement to anisocyanate by heating to reflux in a solvent such as benzene, which isthen reacted with benzyl alcohol to form 11-6. A lactam of formula 11-7can be prepared by removal of the CBZ protecting group from the amine in11-6, followed by cyclization of the amine with the adjacent estergroup. Deprotection of this material provides 11-9, R²═H. Altematively,amide 11-7 can be alkylated by deprotonation with a strong base such assodium hydride, LHMDS, or KHMDS in a suitable solvent such as DMF or THFfollowed by treatment with an alkylating agent such as an alkyl halide,mesylate or tosylate. The product, 11-8, may then be deprotected, asdescribed above, to provide 11-9. One skilled in the art will recognizethat substitution next to the lactam nitrogen could have been introducedby alkylating ester 11-4 or by olefinating 11-1 to give atetra-substituted olefin analogous to 11-3.

[0708] Intermediate enol ethers of formula 12-1 can be prepared bytreating 11-1 (R is an alky( group) with a reagent, such asmethoxymethyl triphenylphosphonium chloride and a strong base, such aspotassium tert-butoxide, in a suitable solvent such as THF. Hydrolysisof an enol ether of formula 12-1 under acidic conditions producesaldehyde 12-2. Reduction of the aldehyde group to an alcohol, forexample with sodium borohydride in methanol, followed by cyclizationconverts 12-2 to a lactone of formula 12-3. Deprotection of thenitrogen, as described above, affords 12-4. One skilled in the art willrecognize that an R^(1A) substituent could have been introduced byalkylating aldehyde 12-2. In addition, substitution next to the lactoneoxygen (R⁹/R¹⁰) could be introduced by olefinating 11-1 to give atetra-substituted olefin and by treating the latter ketone or aldehyde(12-2) with an alkyl metal such as a Grignard reagent.

[0709] Reduction of the ketone in 11-1 (R is an alkyl group) to analcohol with a suitable reducing reagent, such as with sodiumborohydride in methanol, converts 11-1 to 13-1. Hydrolysis of the estergroup in 13-1 according to the method discussed in Scheme 11 producesacid 13-2. Transformation of 13-2 to 13-3 can be achieved by converting13-2 to acyl azides, for instance with DPPA and TEA in a solvent such asbenzene, followed by rearrangement to isocyanates, which then reactintramolecularly with the adjacent alcohol to form carbamate 13-3.Deprotection of 13-3 as described above would provides 13-5 where R² isH. Alternatively, carbamate 13-3 can be alkylated by deprotonation witha strong base such as sodium hydride, LHMDS, or KHMDS in a suitablesolvent such as DMF or THF followed by treatment with an alkylatingagent such as an alkyl halide (R²-halide), mesylate or tosylate. Removalof the protecting group, as described above, transforms 13-4 to 13-5.One skilled in the art will recognize that an R^(1A) substituent couldhave been introduced by treating ketone 11-1 with an alkyl metalreagent, such as methyl magnesium bromide, at a suitable temperature fora Grignard reaction.

[0710] Removal of the carbamate protecting group, Prt, from 11-1 (R isan alkyl group) produces 14-1. Reprotection, such as with a benzyl groupgives 14-2. Treating 14-2 with hydroxylamine yields an oxime of formula14-3. The oxime and ester groups in 14-3 can be reduced to an amine andalcohol, respectively, to form 14-4 with a suitable reducing reagent,such as with LAH in THF. Transformation of 14-4 to a carbamate offormula 14-5 can be achieved by reaction of 14-4 with CDl or anotherphosgene equivalent in the presence of a base like TEA and solvent suchas DME. Deprotection of 14-5 produces 14-7 where R² is H. Alternatively,alkylation of the carbamate as described above (Scheme 13) affords 14-6,which can be deprotected, as described above, to give 14-7.

[0711] Treating 15-1 with a strong base such as sodium hydride in asuitable solvent such as DMF, followed by treatment with an alkylatingagent, such as an alkyl halide, mesylate or tosylate, produces anN-substituted imide of formula 15-2. Reduction of the pyridine ring bycatalytic hydrogenation, such as with Pd on carbon in an ethanolic HClsolution converts 15-2 to 15-3. Protection of the nitrogen, such as witha benzyl group, gives 15-4. A compound of the formula 15-5 can begenerated upon deprotonation of 15-4 with a suitable strong base such asLHMDS in a solvent such as THF at a temperature of about −78° C.,followed by alkylation with an electrophile such as an alkyl halide suchas benzyl bromide. Cleavage of the protecting group, as described above,then gives 15-6.

[0712] Deprotection of 16-1 as described above produces 16-2.

[0713] Condensation of 17-1 (R is an alkyl group) with an amidine in asolvent such as ethanol at an elevated temperature, preferably refluxingsolvent, produces a heterocyclic intermediate of formula 17-2.Deprotection of 17-2, as described above, gives an intermediate offormula 17-3.

[0714] An intermediate amine of formula 18-2 can be prepared from aketone of formula 11-1 (R is an alkyl group) by reductive amination asdescribed above (see Scheme 8). Protection of the secondary amine in18-2 produces 18-3. Intermediate carboxylic acids of formula 18-4 can beprepared by hydrolysis of the ester group of formula 18-3 (see Scheme11). Transformation of 18-4 to 18-5 can be achieved through anintermediate acyl azide as described above (see Scheme 11). Cyclizationof an intermediate of formula 18-5 at a suitable temperature afterremoving Prt′ yields an intermediate urea of formula 18-6. Deprotectionof 18-6 provides 18-8 where R² is H. Alternatively, urea 18-6 can bealkylated by deprotonation with a strong base such as sodium hydride,LHMDS, or KHMDS in a suitable solvent such as DMF or THF followed bytreatment with an alkylafing agent such as an alkyl halide, mesylate ortosylate. Removal of the protecting group transforms 18-7 to 18-8 whereR² and R²′ are each alkyl.

[0715] As illustrated in Scheme 19, reduction of a ketoester of formula19-1, such as with sodium borohydride in methanol, preferably at 0 ° C.,produces an alcohol of formula 19-2. An intermediate of formula 19-3 canbe prepared by protection of the hydroxyl group in an intermediate offormula 19-2 with a suitable protecting group, such as forming atetrahydropyranyl acetal or silyl ether. Transformation of the ester offormula 19-3 to amide 19-5 can be achieved as described above (seeScheme 11). Deprotection of the hydroxy group of 19-5 yields the freealcohol intermediate, which can be oxidized to an intermediate ketone offormula 19-6 with a suitable oxidizing agent, such as pyridiniumchlorochromate or a Swern-type reagent (see Scheme 8). Transformation of19-6 to a cyclized carbamate of formula 19-7 can be achieved by treating19-6 with an alkyl metal, such as a Grignard reagent, in a suitablesolvent such as THF, followed by cyclization. Removal of the protectinggroup then yields 19-9 wherein R² is H. Alternatively, the carbamate of19-7 may be alkylated as described above (see Scheme 13) to afford 19-8,which can then be deprotected to provide 19-9. Those skilled in the artwill recognize that an R^(1A) substituent could have been introduced byalkylating ketoester 19-1.

[0716] An alternate synthesis of lactam 11-7 is illustrated in Scheme20. An alcohol of formula 13-1 can be, converted to an intermediatenitrile of formula 20-1 by first activating the hydroxyl of 13-1 (R isan alkyl group), such as with methanesulfonyl chloride ormethanesulfonic acid in a suitable solvent, such as methylene chloridein the presence of an amine base. Subsequent reaction of 20-1 (LO— is anactivated hydroxyl) with a cyanide salt, such as potassium cyanide, thenyields an intermediate nitrile of formula 20-2, which can be transformedto 11-7 by catalytic hydrogenation of the nitrile to amine, which thenreacts with the ester group to form lactam (11-7). Those skilled in theart will recognize that an R^(1A) substituent could be introduced byalkylating nitrile 20-2.

[0717] Nitriles of formula 21-1 can be prepared from esters, acidhalides and acids of formula 11-1 by a variety of known methods (forexamples, see R. Larock pages 976, 980 and 988 in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, VCHPublishers, 1989).

[0718] Homologation of ketones of formula 21-1 to provide 21-3 asdescribed above (Scheme 12) yields an aldehyde of formula 21-3.Oxidation of the aldehyde group in 21-3, such as with sodiumhypochlorite, provides an acid which can be esterified to give 21-4 by anumber of methods described above (Scheme 6). Reduction of the nitrilegroup in a compound of formula 21-4, such as by catalytic hydrogenationover Pd on carbon, gives an amine which will cyclize to give a lactam offormula 21-5. Deprotection of 21-5 yields 21-7, R² is H. Altematively,alkylation of the amide of formula 21-5 as described above (Scheme 11)yields an N-substituted amide of formula 21-6, which can be deprotectedto provide 21-7. Those skilled in the art will recognize that an R^(1A)substituent could have been introduced by alkylating ester 21-4.

[0719] Intermediate alcohols of formula 22-1 can be prepared by reducingthe ketone and ester groups of 11-1 (R is an alkyl group), such as witha metal borohydride or lithium aluminum hydride in a suitable solventsuch as THF. Selective protection of the primary hydroxyl group of theintermediate of formula 22-1 with a suitable protecting group, such as atrialkylsilyl ether or pivaloyl ester gives a secondary alcohol offormula 22-2. An intermediate nitrile of formula 22-4 can be preparedfrom the alcohol of formula 22-2 by methods described above (see Scheme20). An intermediate nitrile of formula 22-4 can be transformed to anester of formula 22-5 by alcoholysis of nitrile 224, for instance withaqueous HCl or sodium hydroxide in ethanol. Removal of the alcoholprotecting group and reaction of the hydroxyl group with the adjacentester group in 22-5 forms a lactone of formula 22-6. Deprotection asdescribed above yields 22-7. Those skilled in the art will recognizethat an R^(1A) substituent could have been introduced by treating ketone11-1 with the appropriate alkyl metal reagent. Substitution (R⁹, R¹⁰)adjacent to the lactone oxygen could then be introduced by treating theester with the appropriate alkyl metal reagent (the ketone would have tobe reduced if R^(1A) is not O).

[0720] Intermediate α,β-unsaturated nitrites of formula 23-1 can beprepared by olefinating 11-1 (R is an alkyl group) with a reagent suchas cyanomethyltriphenylphosphonium chloride and a strong base, such asKHMDS, in a suitable solvent, such as THF. Reduction of the double bondin 23-1, such as with sodium borohydride in pyridine, produces nitrile23-2. The ester group of formula 23-2 can then be transformed to acarbamate of formula 23-4 by methods described above (see Scheme 11).Alcoholysis of the nitrile of 23-4 in an alcoholic solvent under acidiccondition produces an ester of formula 23-5. A lactam of formula 23-6can be prepared by removal of the CBZ protecting group, followed bycyclization of the amine with the adjacent ester group. Deprotection atthis stage provides 23-8, R² is H. Altematively, alkylation of the amide(according to Scheme 11) provides an N-subsitituted lactam, which can beconverted to 23-8 by deprotection as described above. One skilled in theart will recognize that an R^(1A) substituent could have been introducedby conjugate addition to the unsaturated nitrile (23-1), such as with analkyl cuprate. In addition, R⁹, R¹⁰ substituents can be introduced nextto the lactam carbonyl by alkylating nitrile 23-2.

[0721] As illustrated in Scheme 24, an alcohol of formula 24-1 can beprepared from 19-3 (R is an alkyl group) by reduction of the ester witha reducing reagent such as lithium borohydride in a solvent such as THF.A nitrile of formula 24-2 can be prepared from the alcohols of formula24-1 by methods described above (see Scheme 20). Deprotection of thealcohol of 24-2 followed by oxidation of the hydroxyl as previouslydescribed (see Scheme 19) produces a ketone 24-3. Treating 24-3 with analkyl metal such as a Grignard reagent in a suitable solvent such as THFgives an intermediate of formula 24-4. The cyano group of 24-4 can thenbe converted to an ester by alcoholysis as described above (Scheme 22).Reaction of the tertiary alcohol with the neighboring ester forms alactone which can then be deprotected to give 24-5. One skilled in theart will recognize that an R^(1A) substituent could be introduced byalkylating ester 19-3. In addition, R⁹, R¹⁰ substituents could beintroduced adjacent to the lactone carbonyl by alkylation before finaldeprotection.

[0722] Intermediate of formula 25-1 (LO— is an activated hydroxyl) canbe prepared by selective activation of the primary hydroxyl, forinstance by tosylafion of the less hindered hydroxyl group of 20-1 withtosyl chloride in a suitable solvent. Treating 25-1 with a reagent suchas potassium cyanide in a suitable solvent produces a nitrile of formula25-2. Oxidation of the alcohol (see Scheme 19) of formula 25-2 gives aketone of formula 2-53. Transformation of 25-3 to 25-4 can be achievedby reductive amination as was described above (see Scheme 8). The cyanoamine of formula 25-4 can be converted to a lactam of formula 25-5 bytreating 25-4 with a strong acid or base in a protic solvent such asethanol. Removal of the protecting group on the secondary nitrogen canthen provide lactam 25-6. One skilled in the art will recognize that R⁹,R¹⁰ substituents could be introduced by alkylation of lactam 25-5.

[0723] A lactone of formula 26-1 can be prepared by treating a cyanoalcohol of formula 25-2 with a strong acid such as HCl, or a strong basesuch as NaOH, in a protic solvent such as EtOH. Deprotection, asdescribed above, of the secondary amine of formula 26-1 gives 26-2. Oneskilled in the art will recognize that R⁹, R¹⁰ substituents can beintroduced by alkylation of lactone 26-1.

[0724] Intermediates of formula 27-1 can be prepared by reducing alactam of formula 11-7 to a pyrrolidine with a suitable reducing reagentsuch as borane or lithium aluminum hydride in a suitable solvent such asTHF. Treating 27-1 with an acyl chloride of formula RCOCl (where R is analkyl group) in a suitable solvent produces an intermediate amide offormula 27-2. Removal of the protecting group of the amide of formula27-2 by the method described previously gives an amide of formula 27-3.

[0725] A sulfonamide of formula 27-5 can be prepared by treating 27-1with a sulfonate such as tosyl chloride in the presence of a base suchas pyridine to yield 27-4, followed by removal of the protecting groupas previously described.

[0726] Intermediate diols of formula 28-1 (R is an alkyl group) can beprepared by treating 12-2 with a suitable reducing agent, such aslithium borohydride, in an appropriate solvent, such as THF. Methods forconverting diol 28-1 to furan 28-2 include dehydration under acidicconditions, dehydration with a reagent such as Ph₃P(OEt)₂, or reactionwith a reagent such as toluenesulfonylchloride in the presence of a basefollowed by displacement of the activated alcohol with the remaininghydroxyl group. Removal of the protecting group from 28-2 subsequentlyforms a compound of formula 28-3. One skilled in the art will recognizethat an R^(1A) substituent can be added by alkylating aldehyde 12-2. Inaddition, R⁹, R¹⁰ substituents can be introduced by treating 12-2 withan alkyl metal reagent.

[0727] Intermediate aldehydes of formula 29-1 can be prepared byprotectng the secondary alcohol of 13-1 such as with a silyl ether,followed by reduction of the ester with a reducing reagent such asduisobutylaluminum hydride at −78° C. in a suitable solvent.Alternatively, 13-1 can be reduced to the primary alcohol with a reagentsuch as lithium borohydride₁ and then oxidized to the aldehyde with avariety of reagents described above (see Scheme 8). Homologation ofaldehydes of formula 29-1 to saturated esters of formula 29-3 can beperformed as previously described (see similar homologation of ketonesin Scheme 11). Deprotection of the secondary alcohol of 29-3, followedby cyclization produces lactones of formula 29-4. Deprotection of 29-4will then give 29-5. An R⁹ substituent β to the lactone carbonyl may beintroduced by conjugate addition to unsaturated ester 29-2, such as withan alkyl cuprate. ln addition, R⁹ ₁ R¹⁰ substituents could be introducednext to the lactone carbonyl by alkylating lactone 29-4.

[0728] Intermediate ketones of formula 30-1 can be prepared bydeprotecting the secondary hydroxyl of 29-3 (R is an alkyl group),followed by oxidation of the alcohol to a ketone (see Scheme 19).Reductive amination of 30-1 with a primary amine as previously described(see Scheme 8) produces intermediate 30-3. Cyclization of 30-3 at asuitable temperature yields a lactam of formula 30-4, which can bedeprotected to give 30-5. One skilled in the art will recognize that R⁹,R¹⁰ substituents can be introduced by alkylation of lactam 30-4.

[0729] Homologation of 19-3 (R is an alkyl group) to an ester of formula31-3 can be performed analogously to routes described above (see Scheme29). Removal of Prt′ of 31-3 gives a secondary alcohol which can beoxidized as was previously described (see Scheme 19) to produce a ketoneof formula 31-4. Treating 31-4 with an alkyl metal reagent, such as aGrignard reagent, in a suitable solvent produces intermediate 31-5,which can be cyclized to form lactone 31-6. Removal of the protectinggroup then produces 31-7. One skilled in the art will recognize that anR^(1A) substituent may be introduced by alkylation of ester 19-3. Asubstituent β to the lactone carbonyl may be introduced by conjugateaddition to unsaturated ester 31-2, such as with an alkyl cuprate. Also,R⁹, R¹⁰ substituents can be introduced next to the lactone by alkylationof 31-6.

[0730] Intermediate diols of formula 32-1 can be prepared by reducingthe lactone group of 26-2 with a reagent such as lithium aluminumhydride in a suitable solvent such as THF at a suitable temperature.Selective protection at the less hindered hydroxy group of 32-1, such aswith t-butyldimethylsilyl chloride using triethyiamine in the presenceof DMAP in a solvent such as dichloromethane, produces alcohol 32-2.Conversion of alcohol 32-2 to a nitrile of formula 32-4 may beaccomplished as described above (LO— is an activated hydroxyl group)(see Scheme 20). Alcoholysis of the cyano group of formula 32-4 (seeScheme 22), deprotection of the alcohol, and subsequent lactonizationforms lactones of formula 32-5. Deprotection of an amine of formula 32-5gives a lactone of formula 32-6. One skilled in the art will recognizethat R⁹, R¹⁰ substituents can be introduced β- to the ring oxygen inlactone 32-6 by alkylating lactone 26-2. Substitution α to the lactonering oxygen may be introduced by treating 26-2 with an alkyl metalreagent.

[0731] Intermediate nitriles of formula 33-2 can be prepared byhomologating 12-2 (R is an alkyl group), analogous to the ketonehomologation described in Scheme 23. Conversion. of ester 33-2 tocarbamates of formula 33-4 can be accomplished as described above (seeScheme 11). Alcoholysis of the cyano group of 33-4 as described above(see Scheme 22) and removal of the CBZ protecting group, followed bycyclization of the amine with the adjacent ester group produces a lactamof formula 33-5. Deprotection of 33-5 gives the lactam of formula 33-6.

[0732] Alternatively, alkylation of 33-5 in the usual fashion (seeScheme 11) gives 33-7, which can be deprotected to give 33-8. Oneskilled in the art will recognize that an R^(1A) substituent may beintroduced by alkylating aldehyde 12-2. An R⁹ substitutuent may beintroduced by conjugate addition to the unsaturated nitrile (33-1). R⁹,R¹⁰ substitution can be introduced next to the lactam by alkylation of33-7.

[0733] The homologation of 25-3 to give a lactam of formula 34-5 can beanalogously performed according to the procedures described in Scheme21. One skilled in the art will recognize that an R^(1A) substituent maybe introduced by alkylating 34-4 (R is an alkyl group). R⁹, R¹⁰substitution may be introduced by alkylating nitrile 34-1.

[0734] As illustrated in Scheme 35, catalytic hydrogenation of a nitrileof formula 23-2 (R is an alkyl group) gives an amine, followed bycyclization of the amine with the adjacent ester group to give lactamsof formula 35-1. Deprotection of 35-1 gives 35-3, R² is H. Altematively,alkylation of lactam 35-1 as described above (see Scheme 11) providesN-substituted amides of formula 35-2. Deprotection of 35-2 affords 35-3.One skilled in the art will recognize that an R^(1A) substituent may beintroduced by conjugate addition to the unsaturated nitrile.

[0735] As illustrated in Scheme 36, selective reduction of thecarboxylic acid group of 11-5 to an alcohol, such as by treating 11-5 (Ris an alkyl group) with borane in a suitable solvent, followed bycyclization of the alcohol and ester produces a lactone of the formula36-1. Deprotection of 36-1 then gives 36-2.

[0736] Intermediate alcohols of formula 37-1 can be prepared by reducingthe ketone of 21-1, such as with sodium borohydride in a solvent such asmethanol at a temperature of about 0° C. Reduction of the cyano group toan amine, such as by catalytic hydrogenation, affords aminoalcohol 37-2.Treating 37-2 with a reagent like CDl or other phosgene equivilent inthe presence of a base like TEA (see Scheme 14) produces a cyclizedcarbamate of formula 37-3. Deprotecfion of 37-3 then gives 37-5, R² isH. Alternatively, 37-3 may be alkylated as described above (see Scheme13) to give an N-substituted carbamate of formula 37-4, which isdeprotected to give 37-5. One skilled in the art will recognize that anR^(1A) substituent may be introduced by addition to ketone 21-1.

[0737] Intermediate aminoalcohols of formula 38-1 can be prepared byreducing an ester of formula 18-2 (R is an alkyl group), such as withlithium borohydride. Treating 38-1 with a phosgene equivalent asdescribed in Scheme 14 produces a cyclized carbamate of formula 38-2.Deprotection subsequently provides 38-3.

[0738] Intermediate imines of formula 39-1 can be prepared by condensingthe ketone of 21-1 with a primary amine under dehydrating conditions,such as azeotropic distillation using a solvent like benzene. Catalytichydrogenation to reduce the nitrile and imine converts 39-1 to 39-2.Treating 39-2 with a reagent like CDl, phosgene, or triphosgene in thepresence of a base like TEA produces the cyclized and N-substitutedureas of formula 39-3. Deprotection of this material provides 39-5 wherethe R² attached to the (2)-nitrogen is H. Alkylation of 39-3, such aswith sodium hydride and an alkyl halide produces the N,N′-substitutedureas of formula 39-4, which can be deprotected to provide 39-5 wherethe R² attached to the (2)-nitrogen is an alkyl group.

[0739] As illustrated in Scheme 40, ester 20-2 (R is an alkyl group) canbe converted to carbamate 40-2 as described above (see Scheme 11).Catalytic hydrogenation of 40-2 will reduce the nitrile and cleave theCBZ group to provide a diamine of formula 40-3. Acylating 40-3 with areagent such as CDl, phosgene, or triphosgene in the presence of a baselike TEA produces the cyclized ureas of formula 40-4. Deprotection atthis stage provides 40-6 where each R² is H. Alternatively, alkylationof 40-4, such as by deprotonation with a strong base like sodium hydridefollowed by reaction with an alkylating reagent like an alkyl halide,tosylate or mesylate produces the N,N′-substituted ureas of formula40-5. Deprotection then provides 40-6 where each R² is alkyl. Oneskilled in the art will recognize that an R^(1A) substituent may beintroduced by alkylation of nitrile 20-2.

[0740] Intermediate esters of formula 41-1 (R is an alkyl group) can beprepared by alcoholysis of the cyano group in 40-2 with ethanolic HCl.Reducing the ester group in 41-1, such as with lithium borohydride inTHF produces an alcohol of formula 41-2. Catalytic hydrogenation toremove the CBZ group to yield an amine as previously described converts41-2 to 41-3. Treating 41-3 with a reagent like CDI or other phosgeneequivalent in the presence of a base like TEA produces a carbamate offormula 41-4. Deprotection at this stage provides 41-6 where R²is H.Alternatively, transformation of 41-4 to N-substituted carbamates offormula 41-5 can be achieved by deprotonating 41-4 with a stong basesuch as sodium hydride in a solvent like DMF, followed by alkylationwith a reagent such as an alkyl halide, tosylate or mesylate.Deprotection then converts 41-5 to 41-6 where R² is alkyl.

[0741] Reaction of a ketoester of formula 42-1 with a chiral amine suchas alpha-methylbenzylamine with a suitable aldehyde such asformaldehyde, or reaction of a vinyl ketoester of formula 42-2 with achiral amine such as alpha-methylbenzylamine with a suitable aldehydesuch as formaldehyde, affords a compound of formula 42-3 via a doubleMannich reaction. Compound 42-3 is equivalent to 11-1 where d and e are1, and may be deprotected with a suitable catalyst such as palladium inthe presence of hydrogen to give 42-4. In addition, 42-3 could beisolated as a single diastereomer (by selective cyclization orseparation of diastereomers), thereby providing 42-4 as a singleenantiomer.

[0742] Treatment of a compound of formula 43-1 with a base such assodium hydride in a solvent such as DMF followed by treatment withdiethylcarbonate generates the ethyl ester of compound 43-2 (R is analkyl group). Deprotection of the amine transforms 43-2 into 43-3. Itwill be recognized by one skilled in the art that 19-1 is equivalent to43-3.

[0743] Treatment of a malonic ester of formula 44-1 (R is an alkylgroup) with a base such as sodium hydride in a solvent such as DMF andsubsequent hydrogenolysis of the benzyl group with hydrogen and acatalyst such as palladium in a suitable solvent such as methanolproduces the ester of formula 43-2. Deprotection of the amine generatescompounds of formula 43-3. It will be recognized by one skilled in theart that 19-1 is equivalent to 43-3.

[0744] Treatment of a ketone of formula 45-1 with a secondary amine suchas piperidine in a suitable solvent such as benzene with removal ofwater affords an enamine of formula 45-2 (each R is an alkyl group).Alkylation of the enamine with an alpha-haloester such asethylbromoacetate in a suitable solvent such as benzene or THF using asuitable base such as LDA or NaN(SiMe₃)₂ affords a ketoester of formula45-3. Reduction with a mild reducing agent such as sodium borohydride inmethanol and subsequent cyclization then affords 26-1.

[0745] Treatment of a ketoester of formula 43-3 (R is an alkyl group)with an iodonium salt such as diphenyliodonium trifluoroacetate in asuitable solvent such as t-butanol generates a ketoester of formula 11-1where R¹ is phenyl. See Synthesis, (9), 1984 p. 709 for a detaileddescription.

[0746] Treatment of a ketoester of formula 43-3 with an olefin such asacrylonitrile or nitroethylene generates a ketoester of formula 11-1where R¹ is CH₂CH₂CN or R¹ is CH₂CH₂NO₂.

[0747] Treatment of an ester of formula 43-3 (R is an alkyl group) witha base such as sodium hydride in a solvent such as DMF followed by analkyl halide 48-1 generates a compound of formula 11-1 as illustrated inScheme 48.

[0748] Treatment of a ketoester of formula 43-2 with allyl bromide and asuitable base such as sodium hydride in a suitable solvent such as DMFaffords a ketoester of formula 49-1 (11-1, R² is allyl). Compound 49-1may then be converted to 13-4 as described in Scheme 13. Ozonolysis of13-4 in a suitable solvent such as methylene chloride followed bytreatment with a reducing agent such as dimethylsulfide affords analdehyde of formula 49-2. Oxidation of 49-2 affords a carboxylic acid offormula 49-3. Curtius rearrangement of 49-3, followed by hydrolysis ofthe intermediate isocyanate affords a primary amine of formula 49-4.Treatment of a compound of formula 49-4 with an isocyanate or carbamateaffords a urea of formula 49-5. Deprotection of the nitrogen affordscompounds of formula 49-6 (13-5, R¹ is CH₂NHCONX⁶X⁶). Those skilled inthe art will recognize that other heterocycles, prepared in previousschemes, could be transformed analogously to the conversion of 13-4 to49-6.

[0749] Treatment of a compound of formula 49-2 with a primary amine offormula HNX⁶ affords an imine of formula 50-1. Reduction of a compoundof formula 50-1 affords a compound of formula 50-2. Treatment of acompound of formula 50-2 with an acylating agent affords a compound offormula 50-3. Deprotection of the nitrogen affords compounds of formula50-4 (13-5, R is CH₂CH₂NX⁶COX⁶). Those skilled in the art will recognizethat other heterocycles, prepared in previous schemes, could betransformed in a manner analogous to the conversion of 49-2 to 50-4.

[0750] Treatment of a compound of formula 49-2 with a reducing agentsuch as sodium borohydride affords a compound of formula 51-1. Reactionof 51-1 with an acylating agent such as an isocyanate or carbamateaffords compounds of formula 51-2. Deprotection of the nitrogen affordscompounds of formula 51-3. Those skilled in the art will recognize thatother heterocycles, prepared in previous schemes, could be transformedin a manner analogous to the conversion of 49-2 to 51-3.

[0751] Treatment of a compound of formula 51-1 with a phosphine such astriphenyl phosphine and an azo compound such as diethylazodicarboxylateand an oxindole affords a compound of formula 52-1. Deprotection of thenitrogen affords the compound of formula 52-3. Those skilled in the artwill recognize that other heterocycles, prepared in previous schemes,could be transformed in a manner analogous to the conversion of 49-2 to52-3.

[0752] Treatment of a ketoester of formula 433 with a chiral diol andacid catalyst with removal of water in a suitable solvent such asbenzene affords a chiral ketal like formula 53-1. Alkylafton of 53-1with an alkyl halide in the presence of a base such as LDA followed byacid-catalyzed hydrolysis of the ketal affords chiral ketoesters offormula 53-2. Ketoester 53-2 is a single enantiomer of 11-1 and may behomologated in a similar fashion to give various heterocycles.

[0753] Treatment of a ketoester of formula 43-3 with a chiral amino acidester such as valine t-butyl ester affords a chiral enamine of formula54-1. Alkylation of 54-1 with an alkyl halide in the presence of a basesuch as LDA followed by acid-catalyzed hydrolysis of the enamine affordschiral ketoesters of formula 53-2.

[0754] Salt formation of 7-6 with a chiral acid affords a mixture ofdiastereomeric salts of formula 55-1. Crystallization of thediastereomeric salts affords the acid salt of chiral compounds offormula 55-2. Decomposition of the salt 55-2 with base liberates chiralcompounds of formula 55-3. This resolution scheme could be applied tothe resolution of other HET-bicyclic compounds described above.

[0755] As illustrated in Scheme 56, treatment of 6-4 (p¹ is CO₂Bn) withan alkyl metal reagent like methyl magnesium bromide affords 56-1.Deprotection as usual then affords 56-2.

[0756] Compounds of formula 57-3 can be prepared from known phthalic orhomophthalic anhydrides by methods previously described by Welch,Willard M. (J. Org. Chem 47; 5; 1982; 886-888. J. Org. Chem.; 47; 5;1982; 886-888) or Machida, Minoru et al. (Heterocycles; 14; 9; 1980;1255-1258). Altematively, the analogous phthalimides or homophfhalimidesof formula 57-1 can be treated with the appropriate hydride reagent(e.g., NaBH₄) or organometallic reagent (e.g., methyl Grignard),followed by treatment with sodium or potassium cyanide to produce anintermediate of the formula 57-2. Compounds of formula 57-2 can beconverted to compounds of formula 57-3 as previously described by Welch,Willard M. (J. Org. Chem 47; 5; 1982; 886-888).

[0757] As illustrated in Scheme 58, intermediates of formula 58-4 can beprepared in four steps from compounds of formula 7-1. Compounds offormula 7-1 are treated with a suitable reducing agent such as SuperHydride® in a suitable solvent, preferably THF at a temperature of −20to 50° C., preferably at around 25° C. to give compounds of formula58-1. Amino alcohols of formula 58-1 are then treated with at least twoequivalents of methanesulfonyl chloride and at least two equivalents ofa suitable base, preferably pyridine in a suitable solvent, preferablypyridine at a temperature of −20 to 50° C. preferably around 25° C. togive intermediates of formula 58-2. Treatment of 58-2 with a strongbase, preferably sec-butyllithium at a temperature of around −78° C.followed by warming to a temperature of around 25° C. affordsintermediates of formula 58-3. Removal of the protecting group asdescribed above, transforms 58-3 into 58-4.

[0758] An alternative synthesis of lactam 11-8 is illustrated in Scheme59. An aldehyde of formula 12-2 can be employed in a reductive aminationwith an amine and reducing agent, for example sodiumtriacetoxyborohydride. Subsequent cyclization of the amine with theadjacent ester group affords 11-8. One skilled in the art will recognizethat an R^(1A) substituent could have been introduced adjacent to thealdehyde by alkylating aldehyde 12-2 according to well known procedures.

[0759] Aldehydes of formula 60-1 can be prepared by reducing 7-1 with anagent like diisobutylaluminum hydride at a suitable temperature,preferably −78° C. to 0° C. in a suitable solvent, such as THF,methylene chloride, toluene or ether. This aldehyde may then beconverted to amines of the formula 60-2 by the methods described inScheme 8 to convert 8-3 to 8-5. In addition, an oxime may be formed bytreating the aldehyde with hydroxylamine hydrochloride. Reduction ofthis oxime, such as with Raney-nickel provides 60-2 where R² ishydrogen. Treatment of this material with phosgene, triphosgene,carbonyl diimidazole, or other equivalent in the presence of a base,preferably a tertiary amine base, provides a route to ureas of formula8-7. Those skilled in the art will recognize that R² may have been agroup, such as a benzyl or allyl group, which could be cleaved to give8-7 where R² is hydrogen.

[0760] Alternatively, compounds of the formula 8-7 may be prepared byreducing carbamate protected ester 60-3, for example when R¹═CH₂-2-Pyr,according to well known reduction techniques to afford aldehyde 60-4which may then be converted to an amine, as described above, which isthen reacted with the carbamate at a suitable temperature to provide8-7.

[0761] Olefin 61-1 may be prepared by olefinauing aldehyde 60-1 with areagent such as the anion generated upon treating a trialkyiphosphonoacetate with an appropriate base, such as NaHMDS in a suitable solvent,such as THF. Reduction of the olefin, by methods such as catalytichydrogenation (see Scheme 11) or conjugate reduction with an agent suchas the alkali metal salt of a trialkylborohydride, such as lithiumtri-sec-butylborohydride, provides the compounds of formula 61-2. Thismaterial is cyclized at elevated temperatures in a reaction inertsolvent using cyclization conditions well known to those skilled in theart. Those skilled in the art will recognize that the cyclizationreaction may require the addition of a base such as potassium carbonate.Generally the reaction is carried out at reflux in a solvent such asmethanol. Deprotection of 61-3 affords compounds of formula 61-5 whereR⁹ and R¹⁰═H. Those skilled in the art will recognize that 61-3 can bealkylated under a variety of conditions, such as by treating 61-3 with astrong base, e.g., lithium diisopropylamide or LHMDS in a reaction inertsolvent such as THF at a suitable temperature, preferably −78° C. Theanion generated is treated with alkylating reagents such as alkylhalides or alkyl tosylates, such as methyl iodide, to give 61-4. Thisprocess may be repeated to introduce a second substituent. Deprotectionaffords compunds of formula 61-5. Those skilled in the art willrecognize that a R⁹ substituent can be introduced β to the lactam byconjugate addition to 61-1, such as would be afforded by the use of analkyl cuprate reagent.

[0762] An alternate synthesis of 61-3 is shown above. Reduction ofketoamide 62-1, which is equivalent to 10-2 where R⁹ and R¹⁰ arehydrogen, with a reducing agent such sodium borohydride, in an reactioninert solvent such as methanol at a suitable temperature such as 0° C.affords alcohol 62-2. The alcohol is reacted under standard eliminationconditions well known to those skilled in the art to provide unsaturatedlactam 61-3. Suitable elimination conditions include activating thealcohol, such as by converting it to the corresponding tosylate ormesylate, and then treating the activated alcohol with base at asuitable temperature, for instance with1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing toluene, or bydeprotonating the amide with a strong base such as LHMDS. The alcoholmay also be eliminated at suitable temperatures in the presence of astrong base or strong acid. Those skilled in the art will recognize thatthese conditions may also cleave the protecting group (P). Reduction of62-3, by methods such as catalytic hydrogenation (see Scheme 11) orconjugate reduction with an agent such as the alkali metal salt of atrialklyborohydride, like lithium tri-sec-butylborohydride, will thenprovide 61-3. Those skilled in the art will recognize that a R⁹substituent could have been introduced β to the lactam by conjugateaddition of a reagent, such as a cuprate, to the unsaturated lactam.

[0763] Compounds of formula 63-1 are prepared by deprotonating thealcohol with a strong base such as sodium hydride, LHMDS, KHMS or NaHMDSin a suitable solvent such as DMF or THF followed by treatment with analkylating agent such as an alkyl halide, mesylate or tosylate, forinstance, methyl iodide. The product is then deprotected according tomethods well known to those skilled in the art to provide 63-2.

General Experimental Procedures

[0764] Silica gel was used for column chromatography. Melting pointswere taken on a Buchi 510 apparatus and are uncorrected. Proton andcarbon NMR spectra were recorded on a Varian XL-300, UNITYPlus-400,Bruker AC-300, or Bruker AC-250 at 25° C. Chemical shifts are expressedin parts per million downfield from trimethylsilane. Particle beam massspectra (PBMS) were obtained on a Hewlett-Packard 5989A spectrometerusing ammonia as the source of chemical ionization. The protonatedparent ion is reported as (M+1)⁺. For inital sample dissolutionchloroform or methanol was employed. Atmospheric Pressure ChemicalIonization mass spectra (APcl MS) were obtained on a Plafform II byFisons (now called Micromass Inc.) instrument. They are either run via+APcl (basic method) or −APcl (acid method). The mobile phase is 50:50H₂O:acetonitrile. Either a protonated parent (+APcl) or deprotonatedparent ion (−APcl) is observed (reported as (M+1)⁺ or (M−1)⁻). Forinitial sample dissolution, chloroform or methanol was employed.Thermospray mass spectra (TSMS) were obtained on a Trio-1000 by Fisionsspectrometer using 0.1 M ammonium acetate in ¼ water/methanol. Theprotonated parent ion is reported as (M+1)⁺. For initial sampledissolution chloroform or methanol were employed. TLC analyses wereperformed using E. Merck Kieselgel 60 F254 silica plates visualized(after elution with the indicated solvent(s)) by UV, iodine or bystaining with 15% ethanolic phosphomolybdic acid or cericsulfatelammonium molybdate and heating on a hot plate. The terms“concentrated” and “coevaporated” refer to removal of solvent at wateraspirator pressure on a rotary evaporator with a bath temperature ofless than 40° C.

[0765] The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

[0766] General Procedure A (Peptide coupling using DEC). A 0.2-0.5 Msolution of the primary amine (about 1.0 equivalent) in dichloromethane(or a primary amine hydrochloride and about 1.0-1.3 equivalents oftriethylamine) was treated sequentially with about 1.0-1.2 equivalentsof the carboxylic acid coupling partner, about 1.5-1.8 equivalents of1-hydroxy-7-azabenzotriazole (HOAT) and about 1.0-1.2 equivalents1,2-diethylaminoethyl chloride hydrochloride (DEC) and the mixture wasstirred for about 18-48 hours in an ice bath (the ice bath was allowedto warm, thus the reaction mixture was typically held at about 0-20° C.for about 4-6 hours and about 20-25° C. for the remaining period). Themixture was diluted with ethyl acetate or other solvent as specified,and the resulting mixture washed 1-2 times with 1N NaOH or saturatedsodium bicarbonate (the aqueous phase being sometimes back-washed withethyl acetate), once with brine, dried over Na₂SO₄, and concentratedgiving the crude product which was purified as specified. The carboxylicacid component could be used as the dicyclohexylamine salt in couplingto the primary amine or hydrochloride of the latter, in which case notriethylamine was employed.

[0767] General Procedure B (Peptide coupling using EDC). A 0.04-0.5 Msolution of the primary amine (about 1.0 equivalent) in dichloromethane(or a primary amine hydrochloride and about 1.0-1.3 equivalents oftriethylamine) was treated sequentially with about 1.0-1.2 equivalentsof the carboxylic acid coupling partner, about 1.5-1.8 equivalents of1-hydroxy-7-azabenzotriazole (HOAT), and about 1.0-1.2 equivalents of(stoichiometrically equivalent to the quantity of carboxylic acid)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andthe mixture was stirred for about 18-48 hours in an ice bath (the icebath was allowed to warm, thus the reaction mixture was typically heldat about 0-20° C. for about 4-6 hours and about 20-25° C. for theremaining period). The mixture was diluted with chloroform or othersolvent as specified, and the resulting mixture washed twice with 10%HCl (if the product does not contain a basic functionality that wouldmake the compound soluble in aqueous acidic solution), twice withsaturated sodium bicarbonate solution, 1-2 times with brine, dried overanhydrous magnesium sulfate, and concentrated giving the crude productwhich was purified as specified. The carboxylic acid component could beused as the dicyclohexylamine salt in coupling to the primary amine orhydrochloride of the latter, in which case no triethylamine wasemployed.

[0768] General Procedure C. (Cleavage of a t-BOC-protected amine usingconcentrated HCl). The t-Boc amine was dissolved in a minimum volume ofethanol and the resulting solution was cooled to about 0° C. andconcentrated HCl (typically about 1-4 mL per mmol amine) was added andthe reaction was warmed to room temperature and stirred for about 1 -2.5 hours (the time required for complete disappearance of the startingmaterial to a more polar product as judged by TLC). The resultingsolution or suspension was concentrated, and the residue coevaporatedseveral times with added ethanol to give the free amine which was usedwithout further purification or purified as specified.

[0769] General Procedure D. (Cleavage of a t-BOC-protected amine usingTFA). Trifluoroacetic acid (usually at about 0-25° C.) was added to thet-Boc amine (typically about 10 mL per mmol amine) neat or dissolved ina minimum volume of dichloromethane and the resulting solution wasstirred at about 0° C. or at room temperature for 0.25-2 hours (the timerequired for complete disappearance of the starting material to a morepolar product as judged by TLC). The resulting solution or suspensionwas concentrated, and the residue coevaporated several times with addedmethylene chloride. The residue was then dissolved in ethyl acetate andwashed twice with 1N NaOH and once with brine. The organic phase wasthen dried over Na₂SO₄ and evaporated to give the free amine which wasused without further purification or purified as specified.

[0770] General Procedure E. (Cleavage of a benzyl-protected amine using10% palladium on carbon). The benzyl amine, ethanol (typically about 1mL per every 0.03-0.08 mmol of amine), and 10% palladium on carbon(typically about 20-100% of the weight of the amine used) were combinedand hydrogenated at about 40-50 psi hydrogen on a Parr® shakerovernight. The mixture was then filtered through a bed of Celite®. TheCelite® was washed with ethanol, and the filtrate was concentrated invacuo to give the de-benzylated amine which was used without furtherpurification or purified as specified.

[0771] General Procedure F. (Cleavage of a CBZ-protected amine using 10%palladium on carbon) The CBZ amine, ethanol (typically about 1 mL perevery 0.03-0.08 mmol of amine), and 10% palladium on carbon (typicallyabout 20-100% of the weight of the amine used) were combined andhydrogenated at about 40-50 psi hydrogen on a Parr® shaker overnight.The mixture was then filtered through a bed of Celite®. The Celite® waswashed with ethanol, and the filtrate was concentrated in vacuo to givethe de-benzylated amine which was used without further purification orpurified as specified.

EXAMPLE 1

[0772]

[0773] A. 2-Benzyl-piperazine-1,2,4-tricarboxylic acid 1-benzyl ester4-tert-butyl ester 2-methyl ester

[0774] To a stirred solution of piperazine-1,2,4-tricarboxylic acid1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol),prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193),in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). Thereaction was cooled to about −78° C., and a 1 M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. Thereaction was stirred at about −78° C. for about 1 hour, and then benzylbromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about30 minutes more at about −78° C., then warmed to room temperature andstirred overnight. The reaction was quenched with saturated sodiumbicarbonate solution, and the mixture was extracted three times withethyl acetate. The combined organic layers were extracted twice withwater, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give 31 g of crude product. Purification bysilica gel chromatography using 10-20% ethyl acetate/hexanes as eluentafforded the title compound of part 1-A (20.33 g, 82%): +APcl MS(M−55)⁺413, (M−99)⁺369; ¹H NMR=400 MHz (CDCl₃) δ: 7.37 (arom, m, 5H),7.22 (arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).

[0775] B. 8a-Benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylicacid tert-butyl ester

[0776] To a stirred solution of the title compound of part 1-A (18.06 9,38.5 mmol) in tetrahydrofuran (180 mL) cooled to about 0° C. was added a1 M solution of lithium triethylborohydride in tetrahydrofuran (86.8 mL)over about 10 min. The reaction was allowed to warm to room temperaturefor about 1 hour, after which an additional 5 mL of the 1 M solution oflithium triethylborohydride was added. The reaction was stirred forabout 30 minutes at room temperature, then quenched with saturatedsodium bicarbonate solution followed by the addition of 1N HCl solution.The mixture was then extracted three times with ethyl acetate. Thecombined organic layers were extracted with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to give 20.4 g of a clearoil. Purification by silica gel chromatography using 5% methanol/ethylacetate as eluent afforded 13 g of a solid. Trituration of the solidwith ethyl ether afforded the title compound of part 1-B (9.50 g, 74%):+APcl MS (M−55)⁺277, (M−99)⁺233; ¹H NMR=400 MHz (methanol-d₄) δ:7.30-7.23 (arom, m, 5H), 4.11 (—CO₂—CH₂—, d of d, 2H), 1.50 (BOC, s,9H).

[0777] C. 8a-Benzyl-hexahydro-oxazolo[3,4-a]pyrazin-3-one, hydrochloride

[0778] The title compound of part 1-B (9.5 g, 28.6 mmol) was deprotectedaccording to the method described in General Procedure C to give thetitle compound of part 1-C (7.90 g, ca 100%): +APcl MS (M+1)⁺233; ¹HNMR=400 MHz (methanol-d₄) δ: 7.32-7.23 (arom, m, 5H), 4.22 (—CO₂—CH₂—, dof d, 2H).

[0779] D. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester

[0780] A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol),N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) inanhydrous dichloromethane (1.4 L) was stirred at room temperature forabout 18 hours under nitrogen atmosphere. The reaction mixture waswashed three times each with saturated sodium bicarbonate solution andthen brine. The organic layer was dried over sodium sulfate, filteredand concentrated in vacuo to give the title compound of part 1-D as awhite solid (256 g, 88%): PBMS (M+18)⁺318; ¹H NMR=250 MHz (CDCl₃) δ:4.91 (NH, br s, 1H), 2.84 (—CO(CH₂)₂CO—, s, 4H), 1.67 (Me, s, 6H), 1.48(BOC, s, 9H).

[0781] E.2-tert-Butoxycarbonylamino-3-(3,5-dichloro-benzyloxy)-propionic acid

[0782] To a stirred solution of N-t-butoxycarbonyl-D-serine (10.0 g,48.7 mol) in N,N-dimethylformamide (150 mL) at about 0° C. was addedsodium hydride (4.0 g, 60% dispersion in mineral oil, 99.84 mmol)portionwise. The mixture was stirred for about 30 minutes, and then asolution of 1,3-dichloro-5-chloromethyl-benzene (9.5 mL, 48.7 mmol) inethyl ether (40 mL) was added. The reaction was allowed to slowly warmto room temperature overnight. The reaction was then quenched with 1NNaOH, the mixture extracted three times with dichloromethane. Thecombined organic layers were then washed three times with water, 1N HCl,dried over anhydrous magnesium sulfate, filtered and concentrated invacuo to give crude product. The original basic aqueous layer was thenacidified to about pH 4 with 1N HCl, and the mixture was extracted threetimes with dichloromethane. These three organic layers were combined andwashed three times each with water and brine then dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give anadditional 620 mg of crude product. Both product fractions were combinedand purified by silica gel chromatography using 5% methanol/chloroformas eluent and yielded the title compound of part 1-E (12.39 g, 70%):−APcl MS (M−1)⁻363, (M−3)⁻361; ¹H NMR=400 MHz (CDCl₃) δ: 7.13 (arom, s,3H), 5.42 (NH, d, 1H), 4.50 (CHCO₂H, m, 1H), 4.45 (PhCH₂O, s, 2H), 3.82(CH₂OBz, d of d, 2H), 1.43 (BOC, s, 9H).

[0783] F. 2-Amino-3-(3,5-dichloro-benzyloxy)-propionic acid,hydrochloride

[0784] The title compound of part 1-E (12.39 g, 34.02 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of part 1-F (9.52 g, 93%): −APcl MS (M−1)⁻¹263;¹H NMR=400 MHz (methanol-d₄) δ: 7.35 (arom, m, 3H), 4.59 (PhCH₂O, s,2H), 4.17 (CHCO₂H, m, 1H), 3.93 (CH₂OBz, m, 2H).

[0785] G.2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(3,5-dichloro-benzyloxy)-propionicacid

[0786] A stirred solution of the title compound of part 1-F (9.52 g,31.67 mmol), the title compound of part 1-D (9.5 g, 31.67 mmol), andtriethylamine (13.24 mL, 95.01 mmol) in dioxane/water (100 mL/25 mL) washeated to about 50° C. for about 3 days. The reaction mixture was thenconcentrated in vacuo, diluted with 1N HCl, and then extracted threetimes with aqueous 10% HCl until the mixture was at pH 2. The organiclayer was washed with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give the title compound of part 1-G: -APcl MS(M−1)⁻448, (M−2)⁻447; ¹H NMR=400 MHz (CDCl₃) δ: 7.15 (arom, m, 3H), 5.12(NH, br s, 1H), 4.64 (CHCO₂H, m, 1H), 4.45 (PhCH₂O, s, 2H), 3.70(CH₂OBz, d of d, 2H), 1.49 (Me, s, 3H), 1.48 (Me, s, 3H), 1.38 (BOC, s,9H).

[0787] H.{1-[2-(8a(S)-Benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R)-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0788] According to General Procedure A, the title compound of part 1-C(0.15 g, 0.56 mmol) was coupled to the title compound of part 1-G (0.25g, 0.56 mmol), and the product was purified by silica gel chromatographyusing ethanol/ethyl acetate/hexanes (1:50:40) as eluent to give the lesspolar isomer the title compound of part 1-H (153 mg, 41%): +APcl MS(M)⁺663, (M+2)⁺665, (M−98)⁺565, (M−100)⁺563; ¹H NMR=400 MHz (CDCl₃) δ:7.23-7.10 (arom, m, 8H), 4.41 (PhCH₂O, AB, 2H), 1.42 (Me, s, 3H), 1.38(Me, s, 3H), 1.29 (BOC, s, 9H).

[0789] I.2-Amino-N-[2-(8a(S)-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1(R)-(3,5-dichloro-benzyloxymethyl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0790] The title compound of part 1-H (153 mg, 0.230 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of this Example 1 (128 mg, 93%): +APcl MS(M)⁺563, (M+2)⁺565; ¹H NMR=400 MHz (methanol-d₄) δ: 7.30-7.24 (arom, m,8H), 4.54 (PhCH₂O, s, 2H), 1.58 (Me, s, 3H), 1.57 (Me, s, 3H).

EXAMPLE 2

[0791]

[0792] A. 3-Benzyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester

[0793] The title compound of part 1-A (2.80 g, 5.98 mmol) wasdeprotected according to the method described in General Procedure F togive the title compound of part 2-A as a white foam (1.89 g, 95%): +APclMS (M+1)⁺335, (M−55)⁺279, (M−99)⁺235; ¹H NMR=400 MHz (CDCl₃) δ:7.28-7.18 (arom, m, 5H), 3.66 (Me, s, 3H), 1.40 (BOC, s, 9H).

[0794] B. 3,4-Dibenzyl-piperazine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

[0795] To a solution of the title compound of part 2-A (1.22 g, 3.65mmol) and diisopropylamine (0.63 mL, 3.65 mmol) in acetonitrile (18 mL)was added benzyl bromide (0.45 mL, 3.83 mmol), and the reaction wasstirred at room temperature overnight. The reaction was then heated toreflux for about 5 hours. The solvent was then removed in vacuo, andether was added to the residue. The solid precipitate was removed byfiltration, and the filtrate was concentrated in vacuo to give the titlecompound of part 2-B as a colorless oil (0.87 g, 56%): ¹H NMR=400 MHz(CDCl₃) δ: 7.32-7.13 (arom, m, 10H), 3.65 (Me, s, 3H), 1.37 (BOC, s,9H).

[0796] C. 3,4-Dibenzyl-3-hydroxymethyl-piperazine-1-carboxylic acidtert-butyl ester

[0797] To a solution of the title compound of part 2-B (0.87 g, 2.05mmol) in tetrahydrofuran (10 mL) was added a 1 M solution of lithiumtriethylborohydride in tetrahydrofuran (4.1 mL), with immediateeffervescence observed. The reaction was stirred for about 30 minutes,after which an additional 0.5 mL of the 1 M solution of lithiumtriethylborohydride was added. The reaction was then quenched with a 1NHCl solution (0.5 mL). The mixture was stirred for about 5 minutes, thenbasified with 1N NaOH. The mixture was extracted three times with ethylacetate. The combined organic layers were extracted with brine, driedover sodium sulfate, filtered and concentrated in vacuo to give thetitle compound of part 2-C as a clear oil (0.80 g, 99%): +APcl MS(M+1)⁺397, (M−55)⁺341, (M−99)+297; ¹H NMR=300 MHz (CDCl₃) δ: 7.31-7.25(arom, m, 10H), 1.50 (BOC, s, 9H).

[0798] D. 3,4-Dibenzyl-3-formyl-piperazine-1-carboxylic acid tert-butylester

[0799] To a stirred solution of DMSO (0.312 mL, 4.44 mmol) indichloromethane (10 mL) cooled to about −78° C. was slowly added oxalylchloride (0.193 mL, 2.22 mmol), followed by a solution of the titlecompound of part 2-C (0.80 g, 2.0 mmol) in dichloromethane (3 mL). Thereaction was then allowed to warm to about −30° C. and was stirred forabout 30 minutes. The reaction was re-cooled to about −78° C., andtriethylamine (1.40 mL, 10.1 mmol) was slowly added. The reaction wasstirred for about 5 minutes at about −78° C., then was allowed to warmto room temperature. The reaction was quenched with water and themixture was extracted several times with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound of part2-D as a clear oil (777 mg, 97%): +APcl MS (M)⁺394, (M−56)+338,(M−100)⁺294; ¹H NMR=300 MHz (CDCl₃) δ: 9.72 (aldehyde, s, 1H), 7.30-7.22(arom, m, 10H), 1.40 (BOC, s, 9H).

[0800] E. 3,4-Dibenzyl-3-methylaminomethyl-piperazine-1-carboxylic acidtert-butyl ester

[0801] To a stirred solution of the title compound of part 2-D (0.34 9,0.86 mmol) in methanol (4 mL) cooled to about 0° C. was slowly addedmethylamine hydrochloride (0.29 g, 4.3 mmol), followed by sodium acetate(0.707 g, 8.63 mmol), 3 Å molecular sieves (0.34 g), and sodiumcyanoborohydnde (0.064 9, 1.03 mmol). The reaction was allowed to warmto room temperature and was stirred overnight. The mixture was thenfiltered through a bed of Celite®. The Celite® was washed with methanol,and the filtrate was concentrated in vacuo. The residue was diluted withethyl acetate, and the mixture was extracted twice with 1N NaOH, brine,dried over sodium sulfate, filtered and concentrated in vacuo to give340 mg of a clear oil. Purification by silica gel chromatography using4% methanol/dichloromethane as eluent afforded the title compound ofpart 2-E as a clear oil (214 mg, 61%): +APcl MS (M+1)⁺410, (M−55)⁺354,(M−99)³⁰ 310; ¹H NMR =400 MHz (CDCl₃) δ: 7.32-7.24 (arom, m, 1OH), 2.30(NMe, s, 3H), 1.50 (BOC, s, 9H).

[0802] F. 3-Benzyl-3-methylaminomethyl-piperazine-1-carboxylic acidtert-butyl ester

[0803] The title compound of part 2-E (0.21 g, 0.51 mmol), methanol (15mL), and palladium hydroxide on carbon (0.187 g) were combined andhydrogenated at 45 psi H₂ on a Parr® shaker for approximately 2 days.The mixture was then filtered through a bed of Celite®. The Celite® waswashed with ethanol, and the filtrate was concentrated in vacuo to give180 g of a clear oil. Purification by silica gel chromatography usingammonium hydroxide/methanol/chloroform (0.25:5:95) as eluent yielded thetitle compound of part 2-F as a clear oil (102 mg, 65%): +APcl MS(M+1)⁺320, (M−55)⁺264, (M−99)+220; ¹H NMR=400 MHz (CDCl₃) δ: 7.24-7.17(arom, m, 5H), 2.42 (NMe, s, 3H), 1.40 (BOC, s, 9H).

[0804] G.8a-Benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester

[0805] A stirred solution of the title compound of part 2-F (100 mg,0.31 mmol) and 1,1′-carbonyldimidazole (54 mg, 0.34 mmol) intetrahydrofuran (3 mL) was heated to reflux for about 2.5 hours, andthen allowed to sit at room temperature overnight. The reaction wasquenched with saturated sodium bicarbonate solution, and extracted threetimes with ethyl acetate. The combined organic layers were extractedwith brine, dried over sodium sulfate, filtered and concentrated invacuo to give 142 mg of crude product. Purification by silica gelchromatography using 67% ethyl acetate/hexanes as eluent yielded thetitle compound of part 2-G as a white solid (93 mg, 87%): +APcl MS(M−55)⁺290, (M−99)⁺246; ¹H NMR=400 MHz (CDCl₃) δ: 7.29-7.21 (arom, m,5H), 2.68 (NMe, s, 3H), 1.48 (BOC, s, 9H).

[0806] H. 8a-Benzyl-2-methyl-hexahydro-imidazo[1,5-a]pyrazin-3-one,hydrochloride

[0807] The title compound of part 2-G (89 mg, 0.258 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of part 2-H (77 mg, 77%): +APcl MS (M+1)⁺246; ¹HNMR=400 MHz (CDCl₃) δ: 7.28 (arom, m, 5H), 4.40-2.82 (series of m, 10H),2.70 (NMe, s, 3H).

[0808] I.3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid

[0809] To a solution of D-O-benzylserine (106 g, 0.532 mol) and thetitle compound of part 1-D (160 g, 0.532 mol) in water/dioxane({fraction (250/1000)} mL) was slowly added triethylamine (223 mL, 1.60mol) at room temperature. The reaction was heated to about 50° C. andstirred for about 15 hours under nitrogen atmosphere. The solvent wasthen removed in vacuo, ethyl acetate was added, and the stirred mixturewas acidified with 10% aqueous HCl solution to pH 2-3. The organic layerwas dried over sodium sulfate, filtered and concentrated in vacuo togive the title compound of part 2-1 (200 g, 99%): −APcl MS (M−1)⁻379; ¹HNMR=300 MHz (methanol-d₄) δ: 7.69 (NH, d, 1H), 7.32 (Ph, m, 5H), 4.60(CHCO₂H, m, 1H), 4.51 (CH₂Ph, s, 2H), 3.81 (CH₂OBz, m, 2H), 1.41 (Me, s,6H), 1.40 (BOC, s, 9H).

[0810] -J.{1-[2-(8a(S)-Benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0811] According to General Procedure A, the title compound of part 2-H(39 mg, 0.14 mmol) was coupled to DObenzylserine-N-t-butoxycarbonyl-α-methylalanine (53 mg, 0.14 mmol), andthe product was purified by silica gel chromatography using ethylacetate as eluent to give the title compound of part 2-J (23 mg, 27%):+APcl MS (M+1)⁺608, (M−99)⁺508; ¹H NMR =400 MHz (CDCl₃) δ: 7.28-7.12(arom, m, 10H), 5.28 (PhCH₂O, s, 2H), 2.65 (NMe, s, 3H), 1.44 (Me, s,3H), 1.42 (Me, s, 3H), 1.32 (BOC, s, 9H).

[0812] K.2-Amino-N-[2-(8a(S)-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide. hydrochloride

[0813] The title compound of part 2-J (23 mg, 0.038 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of this Example 2 as a clear glass (206 mg,92%): +APcl MS (M+1)⁺508; ¹H-NMR=400 MHz (methanol-d₄) δ: 7.23 (arom, m,10H), 4.52 (PhCH₂O, s, 2H), 2.58 (NMe, s, 3H), 1.57 (Me, s, 6H).

EXAMPLE 3

[0814]

[0815] A. 2-Pyridin-2-ylmethyl-piperazine-1,2,4-tricarboxylic acid1-benzyl ester 4-tert-butyl ester 2-methyl ester

[0816] A stirred solution of piperazine-1,2,4-tricarboxylic acid1-benzyl ester 4-tert-butyl ester 2-methyl ester (200 g, 529 mol),prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193),in tetrahydrofuran (200 mL) and DMF (1.5 L) was cooled to about −78° C.,and a 0.5 M solution of potassium bis(trimethylsilyl)amide in THF (1.27L) was added. After the above solution had stirred for about one hour,the free base of 2-picolyl chloride was generated by extracting thecorresponding hydrochloride salt (217 g, 1.32 mol) from saturated sodiumbicarbonate solution with methylene chloride. The combined organicextracts were dried (MgSO₄), concentrated, immediately dissolved in DMF(100 mL), and then added dropwise to the enolate containing solution.The reaction was stirred for about 4 hours at about −78° C., then slowlywarmed to room temperature and stirred overnight. The toluene and THFwere removed under reduced pressure. The residue was extracted fromwater (1.5 L) with ethyl acetate (3×1 L), the combined extracts werethen washed with water (1.5 L), dried (MgSO₄) and then concentrated invacuo to give 240 g of crude product of the title compound of part 3-Awhich was carried on to the next step: +APcl MS (M+H)⁺470, (M−Bu+H) 436;¹H NMR=400 MHz (methanol-d₄)

[0817] δ: 8.4 (arom, m, 1H), 7.65-7.2 (arom, m, 7H), 6.94 (arom, m, 1H),5.18 (CbzNCHH, m, 1H), 5.05 (CbzNCHH, m, 1H), 2.54 (m, 1H), 1.41 (Boc,s, 9H).

[0818] B. 3-Pyridin-2-ylmethyl-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester:

[0819] The crude Cbz amine, the title compound of part 3-A, (240 g) inmethanol (1 L), and 10% palladium on carbon (10 g, added in 100 mLwater) were combined and hydrogenated at about 40-50 psi hydrogen on aParro shaker for about 2 days. The mixture was then filtered through abed of diatomaceous earth. The diatomaceous earth was washed withethanol, and the filtrate was concentrated in vacuo to give thede-benzylated amine. Two of the above alkylation/reductions werecombined and purified by silica gel chromatography using 1:1 ethylacetate/hexanes to ethyl acetate to 1:9 methanol/ethyl acetate as eluentand yielded the title compound of part 3-B (217 g, 61%): +APcl(M+1)⁺336; ¹H NMR=400 MHz (methanol-d₄) δ: 8.45 (arom, d, 1H), 7.72(arom, t, 1H), 7.26-7.11 (arom, m, 2H), 4.38 (br s, 1H), 3.57 (MeO, s,3H), 1.41 (Boc, s, 9H).

[0820] C.1,3-Dioxo-8a-pyridin-2-ylmethyl-2-(222-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester

[0821] To a suspension of N,N′-carbonyldiimidazole (69 g, 426 mmol) and2,2,2-trifluoro-ethylamine hydrochloride (71 g, 527 mmol) indichloromethane (500 mL) was added triethylamine (76 mL, 544 mmol) atabout 0° C. dropwise. The reaction was then warmed to room temperatureand stirred at room temperature for about 30 minutes. A solution of thetitle compound of part 3-B (57 g, 170 mmol) in dichloromethane (100 mL)was then added, and the reaction was heated to about 40° C. and thenstirred for approximately 2 days. The reaction was quenched withsaturated sodium bicarbonate solution, and the mixture was thenextracted twice with dichloromethane. The combined organic layers wereextracted twice with water, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give crude product. Purificationby silica gel chromatography using 1:9 to 1:2 to 1:1 ethylacetate/hexanes as eluent afforded the title compound of part 3-C (68.3g, 94%) as an amorphous solid: +APcl MS (M+H)⁺429; ¹H NMR=400 MHz(CDCl₃) δ: 8.4 (arom, d, 1H), 7.54 (arom, t, 1H), 7.12 (arom, t, 1H),7.04 (arom, d, 1H), 4.16-4.00 (CF₃CH₂, m, 2H), 3.41 (PyrCH₂, Ab_(q),2H), 1.50 (Boc, s, 9H).

[0822] D.8a-Pyrdin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahvdro-imidazo[1,5-a]pyrazine-1,3-dione

[0823] The title compound of part 3-C (22.8 g, 53.2 mmol) wasdeprotected according to the method described in General Procedure C togive a pink solid. The residue was extracted from saturated aqueousNaHCO₃ with methylene chloride, the combined organic layers were washedwith brine, dried (MgSO₄) and concentrated to give the title compound ofpart 3-D as a light yellow solid (13.7 g, 78%): +APcl MS (M+H)⁺329; ¹HNMR=400 MHz (CDCl₃) δ: 8.42 (arom, ddd, 1H), 7.55 (arom, td, 1H),7.37-7.07 (arom, m, 2H); 4.15-3.98 (CF₃CH₂, m, 2H), 3.87 (NCHHCH₂, m,1H), 3.79 (CCHHNH, d, 1H), 3.40 (CCHHNH, d, 1H), 3.25 (PyrHH, d, 1H),3.13 (NCHHCH₂, ddd, 1H), 3.02 (NCH₂CHHNH, dd, 1H), 2.74 (PyrCHH, d, 1H),2.66 (NCH₂CHHNH, td, 1H).

[0824] E.(1{(R)-Benzyloxymethyl-2-[1,3-dioxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[0825] According to General Procedure B, 3-D (5.6 g, 15.4 mmol) wascoupled to the title compound of part 2-I (5.84 g, 15.4 mmol), and theproduct was purified by silica gel chromatography using 2:1 ethylacetate/hexanes as eluent to give the title compound of part 3-E(34513-284-1) as a colorless solid (7.3 g, 69%): +APcl MS (M+H)⁺691; ¹HNMR=400 MHz (CDCl₃) δ: 8.35 (arom, m, 1H), 5.23-5.10 (m, 2H), 2.60 (t,1H).

[0826] F.2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pvridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl-2-oxo-ethyl}-2-methyl-propionamide,hydrochloride

[0827] The title compound of part 3-E (410 mg, 0.59 mmol) wasdeprotected according to the method described in General Procedure C togive a colorless solid (6.23 9, 94%).

[0828] HPLC separation of the isomers provided the shorter retainedisomer (2.65 g, 85%): A 70×500 mm Inertsil 15 micron C-8 column(Phenomenex Inc, 2320 W. 205th St., Torrance, Calif. 90501) wasequilibrated with 100% 0.050 M KH₂PO₄ adjusted to pH 2.20 with H₃PO₄.The sample was dissolved in 20 ml mobile phase along with a few drops ofH₃PO₄ and was injected onto the column. The column was eluted at 237.5ml/min., 100% buffer for 1 min., ramped to 75% buffer 25% CH₃CN in 12.5min., and then held for 21.5 min. (total run time 35 min.). The columnwas then rinsed off with 50% water 50% CH₃CN. The product was observedat 254 nm, and was found in fractions 7-11 (24-29 min.). These fractionswere combined, adjusted to a pH of about 7.5 with NaHCO₃ and thenextracted with CHCl₃ (2×1000 ml). The organics were combined, dried(Na₂SO₄) and concentrated to a colorless foam (86.5% diastereomerexcess).

[0829] HPLC analysis was performed on an Hewlett-Packard 1050 systemwith a 1050 DAD, autosampler and solvent delivery system(Hewlett-Packard Company, Analytical Business Center, 2850 CentervilleRoad, Wilmington, Del. 19808-1610). Data was imported into a HP VectraXM series 3 running HP Chemstation ver A.4.02. A 10 μL sample dissolvedin the mobile phase at 1 mg/ml was injected for analysis. A Prodigy3.2×250 mm 5 micron C-8 column (Phenomenex Inc, 2320 W. 205th St.,Torrance, Calif. 90501) was employed with the following solvents:A=0.050 M KH₂PO₄ adjusted to pH 2.20 with H₃PO₄; C acetonitrile. Anisocrafic elution was employed using 65% A and 35% C with a flow rate of0.5 ml/min. detecting at uv, 254nm. The desired enantiomer eluted at 5.7min., while the less desired enantiomer eluted at 6.3 min.

[0830] The desired enantiomer was taken up in ethanol (150 mL), slowlytreated with concentrated aqueous HCl (75 mL) at about 0° C., and thesolvent then removed under reduced pressure. The residue was thenconcentrated from ethanol (4×) to remove residual water. The product wastriturated with ethyl ether to give the title compound of this Example 3(2.72 g, 97%): +APcl MS (M+H)⁺591; ¹NMR=400 MHz (methanol-d₄) δ:8.83-6.90 (NH and arom, series of m, 10H), 5.18-2.90 (aliphatic, seriesof m, 15H), 1.59 (Me, s, 6H); ¹³C NMR=100 MHz (methanol-d₄) δ: 172.4,148.1, 143.4, 130.3, 129.5, 129.0, 127.7, 74.4, 69.7, 64.6, 58.2, 52.3,47.9, 46.9, 40.8, 40.5, 39.2, 36.0, 24.2, 24.1.

EXAMPLE 3a

[0831]

[0832] A.1,3-Dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[15-alpyrazine-7-carboxylic acid tert-butyl ester

[0833] To a solution of the title compound of part 3-D (206 g, 628 mmol)in 10:1 acetonelwater (4.5 L) was added D-tartaric acid (94.2 g, 628mmol). After several minutes a colorless precipitate formed. Afterstirring for about 2 days the solid was collected by filtration (144 g,80% ee). The precipitate was then placed in acetone (2 L) and was heatedfor about 15 hours at about 55° C. The mixture was cooled and the solidcollected by filtration (117 g, 94% ee). The tartrate salt was thenextracted from aqueous sodium bicarbonate with 3:1chloroform/isopropanol to give the free base 3a-A (81.7 g, 78% ee) as anoff-white solid. HPLC analysis of the title compound of part 3a-Aindicated that the material had an enantiomeric excess of 96%: +APcl MS(M+H)⁺329.

[0834] HPLC analysis was performed on an Hewlett-Packard 1050 systemwith a 1050 DAD, autosampler and solvent delivery system. Data wasimported into a HP Vectra XM series 3 running HP Chemstation ver A.4.02.When possible, samples were dissolved in the mobile phase at 1 mg/ml. AChiracel AD 4.6×250 mm column (Chiral Technologies, 730 SpringfieldDrive, P.O. Box 564, Exton Pa. 19341) was employed with the followingsolvents: A =hexane +0.1% diethylamine (v/v); C=isopropanol +0.1%diethylamine (v/v). An isocratic elution was employed using 85% A and15% C with a flow rate of 1 ml/min, detecting at uv, 254nm. The desiredenantiomer eluted at 11.8 min., while the less desired enantiomer elutedat 15.6 min.

[0835] B.(1-{1(R)-Benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl1-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[0836] To a solution of the title compound of part 3a-A at about 0° C.(10.0 g, 30.5 mmol) and the title compound of part 2-1(13.9 g, 36.6mmol) in ethyl acetate (200 mL) was added triethylamine (17 mL, 122mmol), followed by slow addition of a 50% solution of1-propanephosphonic acid cyclic anhydride in ethyl acetate (18.1 mL,30.5 mmol) and the reaction was allowed to warm to room temperature.After about 15 hours, the reaction was extracted from saturated aqueoussodium bicarbonate with ethyl acetate, the combined organics were washedwith water and then brine, dried (MgSO₄), concentrated in vacuo, and theproduct then purified by silica gel chromatography using 0% to 1% to 5%methanol in chloroform as eluent to give the title compound of part 3a-B(19.5 g, 92%) as a colorless foam.

[0837] C.2-Amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl1-2-oxo-ethyl}-2-methyl-propionamide,hydrochloride

[0838] The title compound of part 3-E (17.5 g, 25.3 mmol) wasdeprotected according to the method described in General Procedure C togive a colorless solid. The product was triturated with ethyl ether togive the title compound of this Example 3a (13.6 g, 90%): +APcl MS(M+H)⁺591.

EXAMPLE 4

[0839]

[0840] A.8a-Benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester

[0841] To a solution of the title compound of part 2-A (676 mg, 2.02mmol) in acetone (3 mL) was added methyl isocyanate (0.300 mL, 5.09mmol). The reaction was heated to a gentle reflux and stirred overnightunder nitrogen atmosphere. The reaction was quenched with methanol (1mL), and the mixture was concentrated in vacuo. Purification by silicagel chromatography using 50% ethyl acetate/hexanes as eluent afforded607 mg of crude product, which was recrystallized in ethanol (0.5 mL) togive the title compound of part 4A: +APcl MS (M+1)⁺360; ¹H NMR=300 MHz(CDCl₃) δ: 7.20 (arom., m, 3H), 7.04 (arom., m, 2H), 1.52 (BOC, s, 9H).

[0842] B. 8a-Benzyl-2-methyl-tetrahydro-imidazo[1,5-a]prazine-1,3-dione

[0843] The title compound of part 4-A (150 mg, 0.416 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of part 4-B (113 mg, 92%), MS (APCl) 260.2.

[0844] C.{1-[2-(8a(S)-Benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxvmethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0845] According to General Procedure A, the title compound of part 4-B(101 mg, 0.342 mmol) was coupled to the title compound of part 2-1 (130mg, 0.342 mmol), and the product was purified by silica gelchromatography using methylene chloride with a 0-10% methanol gradientas eluent to give the title compound of part 4-C (88 mg, 41%), MS (PB)622.

[0846] D.2-Amino-N-[2-(8a(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1(R)-benzyloxymethyl-2-oxo-ethy]l-2-methyl-propionamide

[0847] The title compound of part 4-C (82 mg, 0.132 mmol) wasdeprotected according to the method described in General Procedure C,and the product was triturated with ethyl ether to give the titlecompound of this Example 4 (61 mg, 89%). +APcl MS (M+1)⁺522.3.

EXAMPLE 5

[0848]

[0849] A. Piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester:

[0850] According to General Procedure F, piperazine-1,2,4-tricarboxylicacid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (3.0 g, 7.9 mmol)was deprotected to give the title compound of part 5-A (1.8 g, 94%):+APcl MS (M+H)³⁰ 245; ¹H NMR=400 MHz (CDCl₃) δ: 3.73 (Me, s, 3H), 3.43(dd, 1H), 2.73 (t, 1H), 1.45 (BOC, s, 9H).

[0851] B. 2-Methyl-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione,trifluoroacetic acid salt

[0852] To a pre-dried flask was added the title compound of part 5-A(1.0 g, 4.1 mmol), triethylamine (3.99 mL, 28.7 mmol) and anhydrousdichloromethane (30 mL). The mixture was cooled to about 0° C., and thena 1.93 M solution of phosgene in toluene (3.18 mL, 6.10 mmol) was added,and the reaction was stirred at about 0° C. for about 30 minutes. A 2 Msolution of methylamine in methanol (3.07 mL, 6.10 mmol) was added, andthe reaction was stirred for about 30 minutes at about 0° C., and thenallowed to warm to room temperature and stirred overnight. The reactionwas quenched with saturated sodium bicarbonate solution, and the mixturewas then extracted three times with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 0.85 g oft-BOC-protected amine product. The above t-BOC-protected amine productwas deprotected according to the method described in General Procedure Dto give the title compound of part 5-B as the trifluoroacetic acid salt:+APcl MS (M+H)⁺170; ¹H NMR=400 MHz (CDCl₃) δ: 4.45 (dd, 1H), 4.36 (dd,1H), 3.07 (Me, s, 3H).

[0853] C.{1-1(R)-Benzyloxymethyl-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-]pyrazin-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0854] According to General Procedure B, the title compound of part 5-B(50 mg, 0.18 mmol) was coupled to the title compound of part 2-I (60 mg,0.16 mmol), and the product was purified by silica gel chromatographyusing chloroform to 3% methanol/chloroform as eluent to give the titlecompound of part 5-C (46 mg, 42%) as a colorless foam: +APcl MS(M+H)⁺532; ¹H NMR=400 MHz (CDCl₃) δ: 7.37-7.20 (arom, m, 5H), 7.02(CHNH, d, 1H), 3.00 (Me, s, 1H), 2.96 (Me, s, 2H).

[0855] D.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0856] The title compound of part 5-C (46 mg, 0.090 mmol) wasdeprotected according to the method described in General Procedure C,and the product was triturated with ethyl ether to give the titlecompound of this Example 5 (33 mg, 82%): +APcl MS (M+1)⁺432; ¹H NMR400MHz (CDCl₃) δ: 8.70-8.60 (NH, br m, 1H), 2.99 (Me, s, 1H), 2.97 (Me, s,2H).

EXAMPLE 6

[0857]

[0858] A. 2-(4-Fluoro-benzyl)-piperazine-1,2,4-tricarboxylic acid1-benzyl ester 4-tert-butyl ester 2-methyl ester

[0859] Alkylation of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester4-tert-butyl ester 2-methyl ester (10.2 g, 27.0 mmol) with2-fluorobenzyl bromide (5.11 g, 27.0 mmol) was performed analogous tothe preparation of the title compound of part 1-A to afford the titlecompound of part 6-A (2.78 g, 21%): +APcl MS (M−Boc+H)⁺387; ¹H NMR=400MHz (CDCL₃) δ: 7.45-7.30 (arom, br s, 5H), 7.00-6.80 (arom, br m, 4H),5.35-5.05 (br m, 2H), 2.53 (br t, 1H), 1.40 (Boc, s, 9H).

[0860] B. 3-(4-Fluoro-benzyl)-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0861] According to General Procedure F, the title compound of part 6-A(0.249 g, 0.72 mmol) was deprotected to give the title compound of part6-B (0.230 g, 91%): +APcl MS (M+H)⁺353, (M−^(t)Bu+H)⁺297, (M−Boc+H)⁺253;¹H NMR=400 MHz (CDCl₃)

[0862] δ: 7.08-6.90 (arom, m, 4H), 3.62 (Me, s, 3H), 1.41 (Boc, s, 9H).

[0863] C. 4-Acetyl-3-(4-fluoro-benzyl)-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0864] To a solution of the title compound of part 6-B (77 mg, 0.22mmol) and diisopropylethylamine (0.15 mL, 0.87 mmol) in dichloromethane(1 mL) was added acetyl chloride (0.031 mL, 0.44 mmol). The reaction wasstirred for about 1.5 hours, then quenched with saturated aqueousNaHCO₃. Additional methylene chiroride was added and the mixture waswashed twice with saturated NaHCO₃, then brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give the crudeproduct the title compound of part 6-C (86 mg, quantitative): +APcl MS(M−^(t)Bu+H)⁺339, (M−Boc+H)⁺295; ¹H NMR=400 MHz (CDCl₃) δ: 7.10-7.69(arom., m, 4H), 3.70 (MeO, d, 3H), 2.10 (MeCO, d, 2H), 1.42 (BOC, d,9H).

[0865] D.8a-(4-Fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester

[0866] To a stirred solution of the title compound of part 6-C (86 mg,0.22 mmol) in anhydrous tetrahydrofuran (1.5 mL) cooled to about −78° C.under nitrogen atmosphere was added a 1 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.66 mL, 0.66 mmol)dropwise. The reaction was stirred at −78° C. for about 10 minutes, thenthe reaction was quenched with methanol and concentrated in vacuo. Ethylacetate was added, and the mixture was extracted with saturated ammoniumchloride solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give crude product. Purificationby silica gel chromatography using 0-50% ethyl acetate/hexanes as eluentyielded the title compound of part 6-D (53 mg, 67%): −APcl MS (M−H)⁻361;¹H NMR=400 MHz (CDCl₃) δ: 6.94 (arom., d, 4H), 2.66 (CHHPh, d, 1H), 2.01(CHHPh, d, 1H), 1.47 (BOC, s, 9H).

[0867] E.8a-(4-Fluoro-benzyl)-tetrahydro-pyrrolo[1,2-]pyrazine-6,8-dione,hydrochloride

[0868] The title compound of part 6-D (53 mg, 0.15 mmol) was deprotectedaccording to the method described in General Procedure C, and theproduct was triturated with ethyl ether to give the title compound ofpart 6-E (44 mg, quantitative): +APcl MS (M+1)⁺263; ¹H NMR=400 MHz(methanol-d₄) δ: 7.15-6.90 (arom., series of m, 4H), 4.34 (CHHNCO, 1H),2.93 (td, 1H).

[0869] F.(1-{1(R)-Benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[0870] According to General Procedure B. the title compound of part 6-E(44 mg, 0.15 mmol) was coupled to the title compound of part 2-I(56 mg,0.15 mmol), and the product was purified by silica gel chromatography(0-80% ethyl acetate/hexanes) to give desired isomer of the titlecompound of part 6-F (26 mg, 28%), fractions which contained a miture ofthe two diastereomers (20 mg, 22%), followed by the more polar isomer (6mg, 7%): −APcl MS (M−H) 623; For 6-F: ¹H NMR=400 MHz (CDCl₃) δ:7.35-6.85 (arom., series of m, 9H), 5.16 (br m, 1H), 2.03 (d, 1H). Forisomer ¹H NMR=400 MHz (CDCl₃) δ: 7.35-6.55 (arom., series of m, 9H),5.24 (br m, 1H), 1.91 (d, 1H), 1.40 (Boc, s, 9H).

[0871] G.2-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide,hydrochloride

[0872] The title compound of part 6-F (26 mg, 0.042 mmol) wasdeprotected according to the method described in General Procedure C,and the product was triturated with ethyl ether to give the titlecompound of this Example 6 (22 mg, 96%): +APcl MS (M+1)⁺525; ¹H NMR=400MHz (methanol-d₄) δ: 7.40-6.85 (arom., series of m, 9H), 5.15 (t, 1H),4.54 (s, 2H), 2.68 (d, 1H), 1.58 (Me, m, 6H).

EXAMPLE 7

[0873]

[0874] A. 4-Oxo-piperddine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester

[0875] To a mixture of 7.00 g (36.2 mmol) of4-oxo-piperidine-3carboxylic acid methyl ester and 8.82 g (72.3 mmol) of4,4-dimethylaminopyridine in 200 mL of methylene chloride at about 0° C.was added a solution of 7.88 g (36.2 mmol) of di-tert-butyldicarbonatein 150 mL of methylene chloride over about 30 min. The mixture waswarmed to room temperature and then stirred for about 17 h. The mixturewas concentrated and the residue was diluted with chloroform and washedthree times each with 10% aqueous HCl, saturated aqueous sodiumbicarbonate solution and brine, dried over MgSO₄ and concentrated togive 9.18 9 of the title compound of part 7-A as a clear yellow oil.

[0876] B. 3-(R,S)-Benzyl4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0877] To a solution of 5.00 g (19.4 mmol) the title compound of part7-A in 10 mL of DMF was added 745 mg (7.4 mmol) of sodium hydride (60%oil dispersion) and the mixture was stirred at room temperature forabout 15 min. A solution of 3.32 g (19.4 mmol) benzylbromide in 15 mL ofDMF was added to the stirring solution by cannula and the mixture wasstirred for about 42 h at room temperature. The mixture was diluted withethyl acetate and washed once with water and four times with brine,dried over MgSO₄, and concentrated to give 6.0 g of the title compoundof part 7-B as a yellow oil. MS (Cl, NH₃) 348 (MH⁺).

[0878] C.3-Benzyl-4-methoxycarbonylmethylene-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0879] In a pre-dried flask under nitrogen atmosphere was placedtrimethyl phosphonoacetate (0.97 mL, 6.0 mmol) and anhydroustetrahydrofuran (5 mL). The mixture was cooled to about 0° C., andt-butoxide was added dropwise over about 10 minutes, and the reactionwas stirred about 1 hour at about 0° C. A solution of the title compoundof part 7-B (1.058 g, 3.049 mmol) in anhydrous tetrahydrofuran (5 mL)was added via syringe, and the reacton was stirred at room temperatureovernight. The solvent was removed in vacuo, and aqueous 2N HCl wasadded and the mixture was extracted twice with ethyl acetate. Thecombined organic layers were washed with saturated sodium bicarbonateand brine and dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to give the title compound of part 7-C as acolorless liquid (1.407 g, ca 100%): PBMS (M+1)⁺404, (M+18)⁺421,(M−55)⁺348, (M−99)³⁰ 304; ¹H NMR=400 MHz (CDCl₃) δ: 7.25 (arom, m, 3H),7.10 (arom, m, 2H), 5.99 (═CH, brs, 1H), 3.70 (Me, s, 3H), 3.60 (Me, s,3H), 1.40 (BOC, br s, 9H).

[0880] D. 3-Benzyl4-methoxycarbonylmethyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

[0881] The title compound of part 7-C (1.4 g, 3.5 mmol), ethyl acetate(25 mL) and 10% palladium on carbon (280 mg) were combined andhydrogenated at 50 psi H₂ on a Parr® shaker for about 21 hours. Themixture was then filtered through a bed of diatomaceous earth. Thediatomaceous earth was washed with ethyl acetate, and the filtrate wasconcentrated in vacuo. Purification by silica gel chromatography using25% ethyl acetatelhexanes as eluent afforded the title compound of part7-D as a colorless liquid (1.09 g, 79%): PBMS (M+1)⁺406, (M+18)⁺423,(M−99)⁺306; ¹H NMR=400 MHz (CDCl₃) δ: 7.24 (arom, m, 3H), 7.12 (arom, m,2H), 3.69 (Me, s, 3H), 3.57 (Me, s, 3H), 1.42 (BOC, s, 9H).

[0882] E. 3-Benzyl-4-carboxymethyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0883] To a stirred solution of the title compound of part 7-D (1.07 g,2.64 mmol) in methanol (15 mL) at about 0° C. was added a 1M aqueoussolution of lithium hydroxide (3 mL, 3 mmol). The reaction was stirredat room temperature overnight, then additional 1 M aqueous lithiumhydroxide solution (1.0 mL, 1 mmol) was added.

[0884] The reaction was stirred about another 3 hours, then another 1.0mL of the lithium hydroxide solution was added. The reaction was stirredfor about 5 hours more, then concentrated in vacuo. The residue wasquenched with 2N HCl and extracted four times with ethyl acetate. Thecombined organic layers dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo to give the title compound of part 7-E as aviscous oil (951 mg, 92%): −APcl MS (M−1)⁻390; ¹NMR=400 MHz (CDCl₃) δ:7.25 (arom, m, 3H), 7.12 (arom, m, 2H), 3.58 (Me, s, 3H), 1.42 (BOC, s,9H).

[0885] F.3-Benzyl-4-(benzyloxycarbonylamino-methyl)-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

[0886] A solution of the title compound of part 7-E (951 mg, 2.43 mmol),triethylamine (0.341 mL, 2.46 mmol) and diphenylphosphoryl azide (0.593mL, 2.67 mmol) in benzene under nitrogen atmosphere was heated to refluxfor about 45 minutes. Benzyl alcohol (0.503 mL, 4.86 mmol) was added andthe reaction was refluxed overnight. The reaction was cooled to roomtemperature and the solvent was removed in vacuo. Ethyl acetate wasadded, and the mixture was extracted with water, saturated sodiumbicarbonate solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound of part7-F as a yellow liquid (1.44 g, ca 100%): +APcl MS (M−100)⁺397; ¹H NMR=400 MHz (CDCl₃) δ: 7.34-7.12 (arom, m, 10H), 5.09 (NH, s, 1H), 3.68(PhCH₂—O, s, 2H), 3.52 (Me, s, 3H), 1.42 (BOC, br s, 9H).

[0887] G. 4-Aminomethyl-3-benzyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0888] The title compound of part 7-F (1.4 g, 2.8 mmol), ethyl acetate(20 mL) and 10% palladium on carbon (280 mg) were combined andhydrogenated at about 50 psi H₂ on a Parr® shaker for about 20 hours.The mixture was then filtered through a bed of diatomaceous earth. Thediatomaceous earth was washed with ethyl acetate, and the filtrate wasconcentrated in vacuo. The residue was then dissolved in toluene, and acatalytic amount of triethylamine was added. The reaction was refluxedfor about 5 days to form the lactam, with an additional 2-3 drops oftriethylamine added after the first day. The filtrate was thenconcentrated in vacuo. Ethyl acetate was added, and the mixture waswashed with saturated sodium bicarbonate solution, 2N HCl, brine, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo togive 944 mg of a yellow oil. Purification by silica gel chromatographyon a chromatotron using 75% ethyl acetate/hexanes as eluent afforded thetitle compound of part 7-G as a white foam (338 mg, 33 %): +APcl MS(M+1)⁺331, (M−55)⁺275, (M−99)+231; ¹H NMR=400 MHz (CDCl₃) δ: 7.26-7.10(arom, m, 5H), 5.69 (NH, br s, 1H), 3.75 (—NHCH₂—, br d, 2H), 1.47 (BOC,s, 9H).

[0889] H.3a-Benzyl-2-methyl-3oxo-octahydro-pyrrolo[3,4-]pyridine-5-carboxylicacid tert-butyl ester

[0890] To the title compound of part 7-G (168 mg, 0.508 mmol) intetrahydrofuran (3 mL) under nitrogen atmosphere was added sodiumhydride (22 mg, 60% dispersion in oil, 0.55 mmol), and the mixture wasstirred for about 30 minutes at room temperature. Methyl iodide (0.315mL, 5.06 mmol) was added, and the reaction was stirred for about 3 hoursat room temperature. Additional methyl iodide (0.315 mL, 5.06 mmol) wasadded, and the reaction was stirred for about another 3 hours at roomtemperature. The reaction mixture was then concentrated in vacuo. Ethylacetate was added, and the mixture was washed with saturated sodiumthiosulfate solution, brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound of part7-H as a colorless oil (187 mg, ca 100%): +APcl MS (M+1)⁺345,(M−55)⁺289; ¹H NMR=400 MHz (CDCl₃) δ: 7.25-7.15 (arom, m, 5H), 3.64(—NMeCH₂—, br, 2H), 2.70 (NMe, s, 3H), 1.47 (BOC, s, 9H).

[0891] I. 3a-Benzyl-2-methyl-octahydro-pyrrolo[3,4-]pyridin-3-one,hydrochloride

[0892] The title compound of part 7-H (185 mg, 0.537 mmol) in a solutionof 4 M HCl/dioxane (10 mL) was stirred at room temperature for about 4hours. The reaction mixture was concentrated in vacuo to a gummy solid,which was triturated with ethyl ether to give a white solid. The etherwas decanted off and the solid was dried in vacuo to give the titlecompound of part 7-1 (150 mg, 100%): +APcl MS (M+1)⁺245; ¹H NMR=400 MHz(methanol-d₄) δ: 7.29 (arom, m, 3H), 7.18 (arom, m, 2H), 2.70 (NMe, s,3H).

[0893] J.{1-[2-(3a-Benzyl-2-methyl-3-oxo-octahvdro-pyrrolo[3,4-]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0894] To a stirred solution of the title compound of part 2-I (190 mg,0.500 mmol), the title compound of part 7-I (150 mg, 0.534 mmol),1-hydroxy-7-azabenzotriazole (75 mg, 0.55 mmol), and NMM (118 μL, 1.05mmol) in dichloromethane at about 0° C. under nitrogen atmosphere wasslowly added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(106 mg, 0.55 mmol). The reaction was allowed to warm to roomtemperature overnight. The reaction was then concentrated in vacuo.Ethyl acetate was added, and the mixture was extracted with 2N HCl,saturated sodium bicarbonate solution, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 257 mg ofa colorless oil. Purification by silica gel chromatography on achromatotron using 0-2% methanol/ethyl acetate as eluent afforded thetitle compound of part 7-J as a colorless oil (205 mg, 68%): +APcl MS(M+1)⁺607, (M−99)⁺507; ¹H NMR=400 MHz (methanol-d₄) δ: 7.30-7.02 (arom,m,10H), 5.13 (NCHCO, br m,1H), 4.50 (OCH₂Ph, m, 2H), 1.43 (Me, m, 6H),1.38 (BOC, m, 9H).

[0895] K.2-Amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-]pyridin-5-yl)-1)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0896] A solution of the title compound of part 7-J (195 mg, 0.321 mmol)in 4M HCl/dioxane (10 mL) was stirred at room temperature overnight. Thereaction was concentrated in vacuo to a gummy solid, which wastriturated with ethyl ether to give a solid. The solid was collected byfiltration to give the title compound of this Example 7 as a white solid(118 mg, 70%): +APcl MS (M+1)⁺507; ¹H NMR=400 MHz (methanol-d₄) 5:7.32-7.10 (arom, m, 10H), 5.12 (NCHCO, br m, IH), 4.55 (OCH₂Ph, m, 2H),1.60 (Me, m, 6H).

EXAMPLE 8

[0897]

[0898] A. 3-Benzyl4-methoxymethylene-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

[0899] To a suspension of methoxymethyl triphenylphosphonium chloride(9.87 g, 28.8 mmol) in anhydrous tetrahydrofuran (20 mL) was added a 1 Msolution of potassium tert-butoxide in tetrahydrofuran (31.7 mL, 31.7mmol) at room temperature for about 2 hours. The title compound of part7-B (10 g, 28.8 mmol) was then added, and the reaction was stirred atroom temperature overnight. The reaction mixture was diluted with ethylacetate, and washed twice with 10% aqueous HCl solution, saturatedsodium bicarbonate solution, brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give crude product thetitle compound of part 8-A: +APcl MS (M−56)⁺319, (M−100)⁺275; ¹H NMR=300MHz (CDCl₃) δ: 7.28-7.11 (arom, series of m, 5H), 6.61 (C═CH—, s, 1H),3.60 (OMe, s, 3H), 3.55 (OMe, s, 3H), 1.40 (BOC, s, 9H).

[0900] B. 3-Benzyl4-formyl-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

[0901] A solution of the title compound of part 8-A (430 mg, 1.15 mmol)and sodium iodide (343 mg, 2.29 mmol) in tetrahydrofuran (3 mL) wasstirred at room temperature for about 2 days. The reaction mixture wasdiluted with ethyl acetate, and washed twice with saturated sodiumbicarbonate solution, brine, dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to give the title compound of part8-B as a yellow oil (410 mg, 99%): PB MS (M+1)⁺362, (M+18)⁺379, (M−55)306, (M−99) 262; ¹H NMR=250 MHz (CDCl₃) δ: 9.72 (aldehyde, d, 1H),7.26-7.08 (arom, series of m, 5H), 3.60 (OMe, s, 3H), 1.48 (BOC, s, 9H).

[0902] C. 3a-Benzyl-3-oxo-hexahydro-furo[3,4-]pyridine-5-carboxylic acidtert-butyl ester

[0903] To a solution of the title compound of part 8-B (410 mg, 1.14mmol) in methanol (5 mL) at about 0° C. was added sodium borohydride (86mg, 2.3 mmol). The reaction was warmed to room temperature and stirredfor about 2.5 hours. The reaction mixture was cooled to about 0° C., andquenched with saturated ammonium chloride solution. The mixture was thendiluted with ethyl acetate, and washed three times with saturated sodiumbicarbonate solution, twice with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give crude product.Purification by silica gel chromatography using 20-60% ethylacetate/hexanes as eluent afforded the title compound of part 8-C (90mg, 24%): +APcl MS (M−55)⁺276, (M−99)⁺232; ¹H NMR=250 MHz (CDCl₃) δ:7.28-7.17 (arom, series of m, 5H), 1.50 (BOC, s, 9H).

[0904] D. 3a-Benzyl-hexahydro-furo[3,4-]pyridin-3-one

[0905] The title compound of part 8-C (90 mg, 0.27 mmol) was deprotectedaccording to the method described in General Procedure C to give thecrude product as an HCl salt. This crude product was then diluted withchloroform, washed with saturated sodium bicarbonate solution, driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo togive crude product of the title compound of part 8-D as the free amine(50 mg, 81%): +APcl MS (M+1)⁺231; ¹H NMR=250 MHz (methanol-d₄) δ: 7.20(arom, m, 5H), 4.08 (CH₂OCO—, m, 2H).

[0906] E.{1-[2-(3a-Benzyl-3-oxo-hexahydro-furo[3,4-]pyrdridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0907] According to General Procedure B, the title compound of part 8-D(50 mg, 0.22 mmol) was coupled to the title compound of part 2-I (82 mg,0.22 mmol), and the product was purified by silica gel chromatographyusing 50-80% ethyl acetate/hexanes as eluent to give the title compoundof part 8-E (100 mg, 77%): PB MS (M+1)⁺594, (M+18)⁺611; ¹H NMR=250 MHz(CDCl₃) δ: 7.30-6.98 (arom, series of m, 10H), 1.45 (Me, d, 6H), 1.40(BOC, s, 9H).

[0908] F.2-Amino-N-[2-(3a-benzyl-3-oxo-hexahydro-furo[3,4-]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0909] The title compound of part 8-E (100 mg, 0.170 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of this Example 8 (50 mg, 55%): PB MS (M+1)⁺494;¹H NMR=250 MHz (methanol-d₄) δ: 7.31-7.10 (arom, series of m, 10H), 1.57(Me, d, 6H).

EXAMPLE 9

[0910]

[0911] A. 4-Oxo-3-(R,S)-pyrdin-2-ylmethyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

[0912] To a solution of 2.00 g (7.8 mmol) of3-benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-butyl ester, prepared analogously to the preparation of the methylester analog (the title compound of part 7-A), in 32 mL of THF was added468 mg (11.7 mmol) of sodium hydrde (60% oil dispersion) at about 0° C.and the mixture was stirred for about 30 min. A solution of 762 mg (6.0mmol) 2-picolyl chloride in 5 mL of THF was added to the stirringsolution over about 5 min, followed by the addition of 432 mg (2.6 mmol)of potassium iodide. The ice bath was removed and the mixture was heatedfor about 17 h at reflux. The mixture was diluted with ethyl acetate andwashed once with water and once with brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel chromatographyusing (6:4 v/v ether:hexane) followed by (6:4 v/v ethyl acetate:hexane)to give 1.2 g of the title compound of part 9-A. MS (Cl, NH₃) 349 (MH⁺).

[0913] B. 4-Hydroxy-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

[0914] To a stirred solution of the title compound of part 9-A (8.0 g,0.022 mmol) in methanol (80 mL) at 0° C. was added sodium borohydride(0.836, 0.022 mmol) portionwise. The reaction was stirred for about 3hours at room temperature. The reaction was quenched with saturatedammonium chloride solution, the methanol was removed in vacuo, and theaqueous mixture was extracted several times with ethyl acetate. Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to give 10 g of crude product.Purification by silica gel chromatography using 50-80% ethylacetate/hexanes as eluent afforded the title compound of part 9-B (7.3g, 91%): +APcl MS (M+1)⁺365, (M−55)⁺309, (M−99)⁺265; ¹H NMR=300 MHz(CDCl₃) δ: 8.48 (arom, d, 1H), 7.67 (arom, t, 1H), 7.20 (arom, m, 1H),7.00 (arom, br, 1H), 1.44 (BOC, s, 9H), 1.20 (CH₂CH₃, t, 3H).

[0915] C. 4-Hydroxy-3-pyridin-2-ylmethyl-piperidine-1,3-dicarboxylicacid 1- tert-butyl ester

[0916] A solution of the title compound of part 9-B (2.3 g, 6.3 mmol)and aqueous 1N NaOH (32 mL) in ethanol (30 mL) was stirred overnight atroom temperature. The reaction was then stirred overnight at about 35°C. The solvent was removed in vacuo, the aqueous mixture was dilutedwith water and dichloromethane, and then acidified to about pH 4.0-4.8with glacial acetic acid. The organic layer was removed, and the aqueouslayer was extracted several times with dichloromethane. All of theorganic layers were combined and dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to give the title compound of part9-C (2.2 g, 100%): −APcl MS (M−1)⁻335; ¹H NMR=300 MHz (methanol-d₄) δ:8.44 (arom, d, 1H), 7.75 (arom, t, 1H), 7.29 (arom, m, 2H), 1.40 (BOC,s, 9H).

[0917] D.2-Oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-]pyridine-5-carboxylicacid tert-butyl ester

[0918] A solution of the title compound of part 9-C (2.2 g, 6.5 mmol),diphenylphosphoryl azide(1.8 g, 6.5 mmol), and triethylamine (661 mg,6.5 mmol) in benzene (25 mL) was heated to reflux for about 14 hours,then stirred at room temperature for about 2 days. The reaction was thenconcentrated in vacuo. Purification by silica gel chromatography usingethyl acetate/pentane as eluent afforded the title compound of part 9-D(492 mg, 22 %): +APcl MS (M+1)⁺334, (M−55)⁺278; ¹H NMR=300 MHz (CDCl₃)δ: 8.50 (arom, d, 1H), 7.64 (arom, t, 1H), 7.16 (arom, m, 2H), 7.08 (NH,br s, 1H), 1.17 (BOC, s, 9H).

[0919] E.3-Methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-]pyridine-5-carboxylicacid tert-butyl ester

[0920] To a stirred solution of the title compound of part 9-D (494 mg,1.48 mmol) in N,N-dimethylforrnamide was added sodium hydride (43 mg,60% dispersion in mineral oil, 1.8 mmol) at room temperature. Themixture was stirred for about 10 minutes, then methyl iodide (256 mg,1.80 mmol) was added, and the reaction was stirred overnight. Water wasadded to the reaction mixture, and the mixture was extracted severaltimes with ethyl acetate. The combined organic layers were thenback-extracted several times with water. The organic layer was driedover magnesium sulfate, filtered and concentrated in vacuo to give 494mg of crude product. Purification by silica gel chromatography using 60%ethyl acetateihexanes as eluent afforded the title compound of part 9-Eas a crystalline solid (273 mg, 53 %): +APcl MS (M+1)⁺348, (M−55)⁺292,(M−99)⁺248; ¹H NMR=400 MHz (CDCl₃) δ: 8.51 (arom, br, 1H), 7.60 (arom,br, 1H), 7.18 (arom, br m, 2H), 2.85 (NMe, br, 3H), 1.46 (BOC, s, 9H).

[0921] F.3-Methyl-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-]pyridin-2-onedihydrochloride

[0922] To the title compound of part 9-E (270 mg, 0.778 mmol) inanhydrous dichloromethane (1 mL) was added a solution of 4 M HCl/dioxane(1 mL, 4 mmol), and the mixture was stirred for about 4 hours. Thereaction mixture was then concentrated in vacuo to give the titlecompound of part 9-F (220 mg, 89%): +APcl MS (M+1)⁺248; ¹H NMR=300 MHz(methanol-d₄) δ: 8.78 (arom, d, 1H), 8.43 (arom, t, 1H), 8.00 (arom, d,1H), 7.91 (arom, t, 1H), 2.57 (NMe, s, 3H).

[0923] G.{1-[1(R)-Benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0924] To a stirred solution of the title compound of part 9-F (115 mg,0.360 mmol), the title compound of part 2-I (116 mg, 0.360 mmol),triethylamine (101 μL, 0.72 mmol), and 1-hydroxy-7-azabenzotriazole (61mg, 0.45 mmol) in dichloromethane (2 mL) cooled to about −30° C. wasadded 1,2-diethylaminoethyl chloride hydrochloride (69 mg, 0.36 mmol).The reaction was stirred at about −30° C. for about 2 hours, thenallowed to warm slowly to room temperature overnight. The reaction wasthen concentrated in vacuo. Purification by silica gel chromatographyusing ethyl acetate as eluent afforded the title compound of part 9-G(129 mg, 59%): +APcl MS (M+1)⁺610, (M−99)⁺510; ¹H NMR=300 MHz (CDCl₃) δ:8.51 (arom, br d, 1H), 7.57 (arom, br, 1H), 7.25-7.15 (arom, m, 7H),1.42 (Me, s, 6H), 1.38 (BOC, br, 9H).

[0925] H.2-Amino-N-[1(R)-benzyloxvmethyl-2-(3methyl-2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0926] To the title compound of part 9-G (125 mg, 0.205 mmol) inanhydrous dichloromethane (1 mL) was added 4 M HCl/dioxane (1 mL), andthe reaction was stirred at room temperature overnight. The reaction wasconcentrated in vacuo to give the title compound of this Example 9 (133mg, ca 100%): +APcl MS (M+1)⁺510; ¹H NMR=300 MHz (CDCl₃) δ: 8.80 (arom,m, 1H), 8.52 (arom, m, 1H), 8.10 (arom, m, 1H), 8.02 (arom, m 1H),7.35-7.27 (arom, series of m, 5H), 1.62 (Me, s, 3H), 1.59 (Me, s, 3H).

EXAMPLE 10

[0927]

[0928] A. 3-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester,hydrochloride

[0929] To a stirred solution of the title compound of part 7-A (98.1 g,282 mmol) in ethyl ether/ethyl acetate (800 mL/200 mL) at roomtemperature under nitrogen atmosphere was bubbled in HCl gas for about30 minutes. The reaction was stirred for about 1 hour, then HCl gas wasbubbled in for about an additional 30 minutes and the reaction wasstirred for about another 1 hour. HCl gas was bubbled in for about anadditional 1 hour, and then the solid product was collected byfiltration, rinsed with ethyl ether, and dried in vacuo to give thetitle compound of part 10-A as a white powder. (72 g, 90%); ¹H NMR=250MHz (methanol-d₄) δ: 7.29 (arom, m, 3H), 7.09 (arom, m, 2H), 3.81 (Me,s, 3H), 3.74-2.66 (series of m, 8H).

[0930] B. 3-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

[0931] The title compound of part 10-A was suspended in chloroform andwashed twice with saturated sodium bicarbonate solution, dried oversodium sulfate, filtered and concentrated in vacuo to give a waxy solid.This solid was stirred in isopropyl ether (250 mL) overnight, and thenthe solid product was collected by filtration and dried in vacuo to givethe title compound of part 10-B as a white powder (23 g, 76%): TSMS(M+1)⁺248; ¹H NMR=250 MHz (methanol-d₄) δ: 7.22 (arom, m, 3H), 7.10(arom, m, 2H), 3.65 (Me, s, 3H), 3.54-2.35 (series of m, 8H).

[0932] C. 1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

[0933] A solution of the title compound of part 10-B (17.0 g, 68.7mmol), potassium carbonate (19.0 g, 138 mmol), and benzyl bromide (11.8g, 68.7 mmol) in N,N-dimethylformamide (100 mL) was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate andwashed twice with water, brine, dried over sodium sulfate and filtered.The N,N-dimethylformamide was azeotroped off with heptane, and theproduct was concentrated in vacuo to give the title compound of part10-C as a yellow oil (19 g, 82%): PBMS (M+1)⁺338; ¹H NMR=250 MHz (CDCl₃)δ: 7.31 (Ph, m, 5H), 7.21 (Ph, m, 5H), 3.64 (Me, s, 3H), 3.60 (s, 2H),3.41-2.90 (series of m, 8H).

[0934] D. 1,3-Dibenzyl-4-hydroxyimino-peridine-3-carboxylic acid methylester

[0935] To a stirred solution of the title compound of part 10-C (2.1 g,6.2 mmol) and triethylamine (0.90 mL, 6.2 mmol) in methanol (30 mL) wasadded hydroxylamine hydrochloride (433 mg, 6.22 mmol). The reaction wasstirred at room temperature for about 16 hours under nitrogenatmosphere. The reaction mixture was then concentrated in vacuo, dilutedwith dichloromethane, and then quenched with aqueous 10% HCl until themixture was at about pH 2. The organic layer was washed with saturatedsodium bicarbonate solution, brine, dried over sodium sulfate, filteredand concentrated in vacuo to give the title compound of part 10-D as ayellow, hygroscopic solid (1.7 g, 78%): +APcl MS (M+1)⁺353; ¹H NMR=300MHz (methanol-d₄) δ: 7.28-7.17 (arom, m, 1OH), 5.47 (NOH, s, 1H), 3.52(Me, s, 3H), 3.48-2.20 (series of multiplets, 10H).

[0936] E. (4-Amino-1,3-dibenzyl-piperidin-3-yl)-methanol

[0937] To a stirred solution of the title compound of part 10-D (1.59 g,4.51 mmol) in tetrahydrofuran at about 0° C. under nitrogen atmospherewas slowly added a 1 M solution of lithium aluminum hydride (11.28 mL).The reaction was slowly warmed to room temperature and then heated atreflux for about 17 hours. The reaction was then cooled to about 0° C.and quenched with water (8 mL), then aqueous 15% NaOH (24 mL) was slowlyadded, followed by additional water (8 mL). The mixture was filtered,and the solid precipitate was rinsed with ethyl acetate (40 mL). Theorganic layer in the filtrate was separated and washed twice with brine,dried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound of part 10-E as a yellow, hygroscopic solid (1.35 g,57%): +APcl MS (M+1)⁺311; ¹H NMR=250 MHz (methanol-d₄) δ: 7.18 (arom, m,10H), 3.31-1.40 (series of m, 12H).

[0938] F. 4a,6-Dibenzyl-octahydro-3-oxa-1,6diaza-naphthalen-2-one

[0939] A solution of the title compound of part 10-E (980 mg, 3.16mmol), 1,1′-carbonyidiimidazole (2.560 mg, 15.78 mmol), andtriethylamine (0.90 mL, 6.3 mmol) in ethylene glycol dimethyl ether washeated at reflux for about 2 days under nitrogen atmosphere. Thereaction was then cooled to room temperature, and concentrated in vacuo.The mixture was diluted with chloroform (150 mL), and washed with water(30 mL) and then brine (30 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. Purification by silica gelchromatography using 75% ethyl acetate/hexanes as eluent afforded thetitle compound of part 10-F (410 mg, 39%): +APcl MS (M+1)⁺337; ¹HNMR=300 MHz (CDCl₃) δ: 7.40-7.00 (arom, series of m, 10H), 6.34 (NH, brs, 1H), 3.75 (d of d, 2H), 3.51 (s, 2H), 3.39 (m, 2H), 3.11 (br d, 1H),2.68 (d of d, 2H), 2.14-1.50 (series of m, 4H).

[0940] G. 4a-Benzyl-octahydro-3-oxa-1,6diaza-naphthalen-2-one

[0941] The title compound of part 10-F (347 mg, 1.03 mmol), ethanol (50mL), water (10 mL), and 10% palladium on carbon (347 mg) were combinedand hydrogenated at 45 psi H₂ on a Parr® shaker ovemight. The mixturewas then filtered through a bed of diatomaceous earth. The diatomaceousearth was washed with ethanol (200 mL), and the filtrate wasconcentrated in vacuo. Purification by silica gel chromatography using75-100% ethyl acetate/hexanes as eluent afforded the title compound ofpart 10-G as a white solid (130 mg, 53%): +APcl MS (M+1)⁺247; ¹H NMR=250MHz (methanol-d₄) δ: 7.29 (Ph, m, 5H), 3.78 (s, 1H), 3.35 (s, 2H),3.22-1.68 (series of m, 8H).

[0942] H.{1-[2-(4a-Benzyl-2-oxo-hexahydro-3-oxa-1,6-diaza-naphthalen-6-yl)-1-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester:

[0943] A solution of the title compound of part 10-G (125 mg, 0.507mmol), 1-hydroxy-7-azabenzotriazole (103 mg, 0.762 mmol), the titlecompound of part 2-1 (290 mg, 0.762 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (107 mg, 0.558 mmol) inanhydrous dichloromethane (20 mL) was stirred at room temperatureovernight under nitrogen atmosphere. The reaction mixture was dilutedwith dichloromethane, and the solution was extracted with saturatedsodium bicarbonate solution and then brine. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. Purification bysilica gel chromatography using 5% methanol/dichloromethane as eluentafforded the title compound of part 10-H as a white solid (93 mg, 30%):+APcl MS (M+1)⁺609, (M−99)⁺509; ¹H NMR=250 MHz (CDCl₃) δ: 7.25 (arom, m,10H), 1.50-1.40 (Me, BOC, 15H).

[0944] I.2-Amino-N-[2-(4a-benzyl-2-oxo-hexahydro-3-oxa-1,6-diaza-naphthalen-6-yl-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0945] To a stirred solution of the title compound of part 10-H (89 mg,0.15 mmol) in ethanol (30 mL) was added concentrated hydrochloric acid(8 mL) at room temperature. The reaction was stirred for about 30minutes, then concentrated in vacuo. The residue was dissolved inmethanol (1 mL), ethyl acetate was added, and the product precipitatedout as a solid. The solvent was removed in vacuo to give the titlecompound of this Example 10 as a white solid (83 mg, 100%): +APcl MS(M+1)⁺509; ¹H NMR=250 MHz (methanol-d₄) δ: 7.20 (arom, m, 10H), 1.58(Me, br s, 3H) 1.50 (Me, br s, 3H).

EXAMPLE 11

[0946]

[0947] A. 2-Methyl-pyrrolo[3,4-]pyridine-1,3-dione

[0948] To a stirred solution of 3,4-pyridinedicarboximide (10.0 9, 67.5mmol) in N,N-dimethylformamide was added sodium hydride (1.55 g, 60%dispersion in mineral oil, 67.5 mmol) at room temperature. The mixturewas stirred for about 30 minutes, then methyl iodide (9.58 g, 67.5 mmol)was added, and the reaction was stirred overnight. Ethyl acetate wasadded to the reaction mixture, and the mixture was extracted once withwater, twice with brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo (azeotropingexcess N,N-dimethylformamide with heptanes) to give crude product.Purification by silica gel chromatography using 0-5%methanol/dichloromethane as eluent afforded the title compound of part11-A as an off-white solid (5 g, 46%): PB MS (M+1)⁺163; ¹H NMR=250 MHz(CDCl₃) δ: 9.11 (arom, s, 1H), 9.08 (arom, d, 1H), 7.75 (arom, d, 1H),3.20 (Me, s, 3H).

[0949] B. 2-Methyl-hexahydro-pyrrolo[3,4-]pyridine-1,3-dione,hydrochloride

[0950] The title compound of part 11-A (1.00 g, 6.17 mmol), ethanol (20mL), 3N HCl (5 mL), and 10% palladium on carbon (1.0 g) were combinedand hydrogenated at about 45 psi H₂ on a Parr® shaker overnight. Themixture was then filtered through a bed of diatomaceous earth. Thediatomaceous earth was washed with ethanol, and the filtrate wasconcentrated in vacuo to give the title compound of part 11-B as a whitesolid (1.35 g, 100%): PB MS (M+1)⁺169; ¹H NMR=300 MHz (methanol-d₄) δ:2.98 (Me, s, 3H).

[0951] C.2-Methyl-1,3-dioxo-octahydro-pyrrolo[3,4-]pyridine-5-carboxylic acidtert-butyl ester

[0952] To a stirred solution of the title compound of part 11-B (1.27 g,6.20 mmol) and 4-dimethylaminopyridine (1.51 g, 12.4 mmol) indichloromethane (100 mL) cooled to about 0° C. was added a solution ofdi-tert-butyl dicarbonate (1.35 g, 6.20 mmol) in dichloromethanedropwise. The reaction was then allowed to warm slowly to roomtemperature overnight. The reaction was concentrated in vacuo. Ethylacetate was added to the reaction mixture, and the mixture was extractedtwice with 10% HCl, twice saturated sodium bicarbonate solution, andtwice with brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give the title compoundof part 11-C as a light yellow oil (1.2 g, 72%): PB MS (M+1)⁺269,(M+18)⁺286; ¹H NMR=300 MHz (CDCl₃) δ: 2.85 (Me, s, 3H), 1.34 (BOC, s,9H).

[0953] D.3a-Benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-]pvridine-5carboxylicacid tert-butyl ester

[0954] To a stirred solution of the title compound of part 11-C (600 mg,2.24 mmol) in tetrahydrofuran (10 mL) cooled to about −78° C. was addeda 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(2.33 mL) was slowly added over about 10 minutes. The reaction wasstirred at about −78° C. for about 30 minutes, and then benzyl bromide(0.28 mL, 2.3 mmol) was added. The reaction was allowed to slowly warmto room temperature and was stirred for about 3 days. The reaction wasconcentrated in vacuo, and water was added. The mixture was extractedtwice with ethyl acetate. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to givecrude product. Purification by silica gel chromatography using 15-100%ethyl acetate/hexanes as eluent afforded the title compound of part 11-D(470 mg, 59%): PB MS (M+1)⁺359, (M+18)⁺376; ¹H NMR=300 MHz (CDCl₃) δ:7.20 (arom., m, 3H), 7.06 (arom., m, 2H), 2.80 (Me, s, 3H), 1.40 (BOC,s, 9H).

[0955] E. 3a-Benzyl-2-methyl-hexahydro-pyrrolo[3,4-]pyridine-1,3-dione,hydrochloride

[0956] The title compound of part 1 1-D (450 mg, 1.26 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of part 11-E (370 mg, 99%): PB MS (M+1)⁺259; ¹HNMR=250 MHz (methanol-d₄) δ: 7.28 (arom., m, 3H), 7.14 (arom., m, 2H),2.70 (Me, s, 3H).

[0957] F.{1-[2-(3a-Benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-]pyridin-5-yl)-1(R)-benzyloxvmethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}carbamicacid tert-butyl ester

[0958] According to General Procedure B. the title compound of part 11-E(150 mg, 0.51 mmol) was coupled to the title compound of part 2-I (193mg, 0.51 mmol), and the product was purified by silica gelchromatography using 50-100% ethyl acetate/hexanes as eluent to give thetitle compound of part 11-F (180 mg, 57%): PB MS (M+1)⁺621, (M+18)⁺638;¹H NMR=250 MHz (CDCl₃) δ: 7.30-6.90 (arom., series of m, 10H), 1.44 (Me,s, 6H), 1.40 (BOC, s, 9H).

[0959] G.2-Amino-N-[2-(3a-benzyl-2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0960] The title compound of part 11-F (180 mg, 0.29 mmol) wasdeprotected according to the method described in General Procedure C togive the titile compound of this Example 11 (120 mg, 74%): PB MS(M+1)⁺521; ¹H NMR=300 MHz (methanol-d₄) δ: 7.30-7.10 (arom., series ofm, 10H), 1.55 (Me, br s, 6H).

EXAMPLE 12

[0961]

[0962] A. 2-Ethyl-5,6,7,8-tetrahydro-3H-pyrido[3.4-]pyrimidin-4-one7-Benzyl-2-ethyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (270mg, 1.00 mmol), prepared by the method of Lazar et al. (J. Heterocycl.Chem. 1990, 27, 1885), was de-benzylated according to the methoddescribed in General Procedure D to give the title compound of part 12-Aas a white powder (160 mg, 89%): PB MS (M+1)⁺180; ¹H NMR=300 MHz(methanol-d₄) δ: 3.70 (—NCH₂, s, 2H), 3.20 (—NCH₂—, t, 2H), 2.58 (CH₂Me,t, 2H), 2.48 (—CH₂—C—CO, br t, 2H), 1.25 (Me, t, 3H).

[0963] B. {1-[1-Benzyloxymethyl-2-(2-ethyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-]pyrimidin-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}carbamicacid tert-butyl ester

[0964] According to General Procedure B, the title compound of part 12-A(80 mg, 0.45 mmol) was coupled to the title compound of part 2-1 (170mg, 0.450 mmol), and the product was purified by silica gelchromatography using 0-8% methanol dichloromethane as eluent to give thetitle compound of part 12-B (160 mg, 66%): PB MS (M+1)⁺542, (M−99)⁺442;¹H NMR=250 MHz (CDCl₃) δ: 7.21 (arom., m, 5H), 1.50 (Me, d, 6H), 1.40(BOC, d, 9H), 1.25 (—CH₂CH₃, d of t, 3H).

[0965] C.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-]pyrimidin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0966] The title compound of part 12-B (160 mg, 0.300 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of this Example 12 as an off-white powder (100mg, 70%): PB MS (M+1)⁺442; ¹H NMR=250 MHz (methanol-d₄) δ: 7.30 (arom.,m, 5H), 1.58 (Me, s, 6H), 1.40 (CH₂CH₃, t, 3H).

EXAMPLE 13

[0967]

[0968] A.6-Benzyl-2-ethyl-5,6,7,8-tetrahydro-3H-pyrido[4,3-]pyrimidin-4-one

[0969] To a stirred solution of 1-benzyl-3-carboethoxy-4-piperidonehydrochloride (10 g, 34 mmol), prepared by the method of Lazar et al.(J. Heterocycl. Chem. 1990, 27, 1885), in ethanol (200 mL) was addedpropylamidine hydrochloride (4.01 mg, 36.9 mmol), followed by sodiumhydride (2.32 mg, 60% dispersion in mineral oil, 101 mmol). The reactionwas heated to about 100° C. and stirred for about 2 days, then cooled toroom temperature and stirred for about 1 day. The reaction wasconcentrated in vacuo, and ethyl acetate was added. The mixture wasextracted once with water, twice with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give crudeproduct. Purification by silica gel chromatography using 2-10%methanol/dichloromethane as eluent afforded the title compound of part13-A (1.9 g, 21%): PB MS (M+1)⁺270; ¹H NMR=250 MHz (methanol-d₄) δ: 7.32(arom., m, 5H), 2.60 (CH₂CH₃, q, 2H), 1.28 (CH₂CH₃, t, 3H).

[0970] B. 2-Ethyl-5,6,7,8-tetrahydro-3H-pyrido[4,3-]pyrimidin-4-one

[0971] The title compound of part 13-A (1.0 g, 3.7 mmol) wasde-benzylated according to the method described in General Procedure Dto give the title compound of part 13-B (640 mg, 97%): PB MS (M+1)⁺180;¹H NMR=300 MHz (methanol-d₄) δ: 2.60 (CH₂CH₃, q, 2H), 1.28 (CH₂CH₃, t,3H).

[0972] C.{1-[1-Benzyloxymethyl-2-(2-ethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-]pyrimidin-6-yl)-2-oxo-ethylcarbamoy]-1-methyl-ethyl}carbamicacid tert-butyl ester

[0973] According to General Procedure B. the title compound of part 13-B(140 mg, 0.78 mmol) was coupled to the title compound of part 2-I (298mg, 0.78 mmol), and the product was purified by silica gelchromatography using 2-10% methanovdichloromethane as eluent to give thetitle compound of part 13-C (270 mg, 64%): PB MS (M+1)⁺542, (M−99)⁺442;¹H NMR=300 MHz (methanol-d₄) δ: 7.20 (arom., m, 5H), 1.38 (BOC, s, 9H),1.31 (Me, s, 6H), 1.27 (—CH₂CH₃, m, 3H).

[0974] D.2-Amino-N-[1(R)-benzyloxymethyl-2-(2-ethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-]pyrimidin-6-yl)-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride

[0975] The title compound of part 13-C (250 mg, 0.46 mmol) wasdeprotected according to the method described in General Procedure C togive the title compound of this Example 13 (200 mg, 91%): PB MS(M+1)⁺442; ¹H NMR=250 MHz (methanol-d₄) δ: 7.28 (arom., m, 5H), 1.60(Me, s, 6H), 1.40 (CH₂CH₃, t, 3H).

[0976] The following abbreviations and notations are used in the Tablesbelow.

[0977] Abbreviation:

[0978] Me—methyl

[0979] Et—ethyl

[0980] Ph—phenyl

[0981] Pyr—pyridyl

[0982] A =Mass Spec. Method is ⁻AP_(c)l

[0983] B=Mass Spec. Method is PB

[0984] C =Mass Spec. Method is ^(+AP) _(c)l

EXAMPLES 14-58

[0985] The compounds of examples 14-58 were synthesized in a manneranalogous to the procedures described for Examples 3, 3a, 4 and 5, usingthe appropriate starting materials.

Ex. # R² R¹ R″ isomer MS 14 Me CH₂Ph OCH₂Ph d2 523^(C) 15 Me CH₂PhOCH₂Ph d1 522^(B) 16 Me CH₂-4-F—Ph OCH₂Ph d2 540^(C) 17 Me CH₂-4-F—PhOCH₂Ph d1 540^(C) 18 Me CH₂Ph OCH₂-2-Pyr d1,2 523^(B) 19 Me CH₂-3-PyrOCH₂Ph d1,2 523^(B) 20 Me CH₂Ph OCH₂-3-Pyr d1,2 523^(C) 21 Me CH₂-2-PyrOCH₂Ph d1,2 523^(C) 22 Me CH₂Ph 2-Indole d1,2 531^(C) 23 Me CH₂PhOCH₂-4-Thiazole d1,2 529^(C) 24 Et CH₂Ph OCH₂-3,4-di-F—Ph d1,2 572^(C)25 Me CH₂Ph OCH₂-2,4-di(CF₃)Ph d2 658^(C) 26 CF₃CH₂ CH₂-4-CF₃—Ph OCH₂Phd1,2 657^(C) 27 CF₃CH₂ CH₂-4-CF₃—Ph 2-Indole d1,2 667^(C) 28 CF₃CH₂CH₂-4-F—Ph OCH₂Ph d1,2 608^(C) 29 CF₃CH₂ CH₂-4-F—Ph OCH₂-2,4-di-F—Phd1,2 644^(C) 30 Me CH₂-4-F—Ph 3-Indole d1,2 549^(C) 31 Me CH₂-4-F—PhOCH₂-2,4-di-F—Ph d1,2 576^(C) 32 Me H 3-Indole d1,2 441^(C) 33 CF₃CH₂ HOCH₂-2,4-di-F—Ph d1,2 468^(C) 34 Me H OCH₂-2,4-di-F—Ph d1,2 536^(C) 35CF₃CH₂ CH₂-3,4-di-F—Ph 3-Indole d1,2 635^(C) 36 CF₃CH₂ CH₂-3,4-di-F—PhOCH₂Ph d1,2 626^(c) 37 CF₃CH₂ CH₂-3,4-di-F—Ph OCH₂-2,4-di-F—Ph d1,2662^(C) 38 Me CH₂Ph OCH₂-3,4-di-F—Ph d2 558^(C) 39 CF₃CH₂ CH₂-3-F—Ph3-Indole d2 617^(C) 40 CF₃CH₂ CH₂-3-F—Ph 3-Indole d1 617^(C) 41 CF₃CH₂—CH₂-2-F—Ph OCH₂Ph d1,2 591^(C) 42 Me CH₂-2-Pyr OCH₂Ph d2 523^(C) 43 MeH OCH₂Ph d1,2 432^(C) 44 CF₃CH₂ CH₂Ph OCH₂Ph d2 590^(C) 45 CF₃CH₂ CH₂PhOCH₂Ph d1 590^(C) 46 CF₃CH₂ CH₂-2-Pyr OCH₂Ph d1 591^(C) 47 CF₃CH₂CH₂-2-Pyr OCH₂Ph d2 591^(C) 48 CF₃CH₂ CH₂-3-Pyr OCH₂-2,4-di-F—Ph d1,2627^(C) 49 CF₃CH₂ CH₂-3-Pyr OCH₂-2-CF₃—Ph d1,2 659^(C) 50 CF₃CH₂CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 625^(C) 51 CF₃CH₂ CH₂-3-Pyr OCH₂-2-Pyr d1,2592^(C) 52 CF₃CH₂ CH₂-3-Pyr OCH₂-4-F—Ph d1,2 609^(C) 53 CF₃CH₂ CH₂-3-PyrOCH₂-2,3-di-F—Ph d1,2 626^(C) 54 CF₃CH₂ CH₂-3-Pyr OCH₂-3-Pyr d1,2592^(C) 55 CF₃CH₂ CH₂-2-Pyr OCH₂-2,4-di-F—Ph d2 627^(C) 56 CF₃CH₂CH₂-2-Pyr OCH₂-2-CF₃—Ph d2 659^(C) 57 CF₃CH₂ CH₂-2-Pyr OCH₂-2-Pyr d2 59258 CF₃CH₂ CH₂-2-Pyr OCH₂-4-Cl—Ph d2 625^(C)

EXAMPLES 59-60

[0986] The compounds of examples 59-60 were synthesized in a manneranalgous to the procedures described for Examples 3, 3a, 4 and 5, usingthe appropriate starting materials.

Ex. # R² R¹ R″ MS 59 Me CH₂-4-F—Ph 1-Naphthalene 586^(C) 60 CF₃CH₂CH₂-3,4-di-F—Ph 1-Naphthalene 672^(C)

EXAMPLES 61-63

[0987] The compounds of examples 61-63 were synthesized in a manneranalogous to the procedures described for Example 2, using theappropriate starting materials.

CP# R″ isomer MS 61 OCH₂Ph d2 508^(C) 62 OCH₂Ph d1 508^(C) 63 3-Indoled1,2 517^(C)

EXAMPLES 64-95

[0988] The compounds of examples 64-95 were synthesized in a manneranalogoud to the procedures described for Example 1, using theappropriate starting materials.

Ex. # R¹ R″ isomer MS 64 CH₂Ph OCH₂Ph d2 495^(C) 65 CH₂Ph OCH₂Ph d1495^(C) 66 CH₂-2-Pyr OCH₂Ph d1,2 495^(C) 67 CH₂-4-Thiazole OCH₂Ph d1,2501^(C) 68 CH₂-5-Thiazole OCH₂Ph d1,2 502^(C) 69 CH₂Ph OCH₂-2-Pyr d2496^(C) 70 CH₂Ph OCH₂-2-Pyr d1 496^(C) 71 CH₂-4-Pyr OCH₂Ph d1,2 496^(C)72 CH₂Ph OCH₂-4-Pyr d1,2 496^(C) 73 CH₂Ph OCH₂-2-(Me)Ph d2 509^(C) 74CH₂Ph OCH₂-2-(Me)Ph d1 509^(C) 75 CH₂Ph OCH₂-2,4-di-F—Ph d2 531^(C) 76CH₂Ph OCH₂-2,4-di-F—Ph d1 531^(C) 77 CH₂Ph OCH₂-3-Pyr d1,2 496^(C) 78CH₂Ph OCH₂-3-(Me)Ph d2 509^(C) 79 CH₂Ph OCH₂-3-(Me)Ph d1 509^(C) 80CH₂-3-Pyr OCH₂Ph d1,2 496^(C) 81 CH₂Ph 3-indole d1,2 504^(C) 82 CH₂PhOCH₂-4-Thiazole d1,2 502^(C) 83 CH₂-4-(CF₃)-Ph 3-Indole d1,2 572^(C) 84CH₂-4-(CF₃)-Ph OCH₂Ph d1,2 563^(C) 85 CH₂Ph OCH₂-3,5-di(CF₃)—Ph d2631^(C) 86 CH₂Ph OCH₂-3,5-di(CF₃)—Ph d1 631^(C) 87 CH₂PhOCH₂-3,5-di-Cl—Ph d2 563^(C) 88 CH₂Ph OCH₂-3,5-di-Cl—Ph d1 559^(C) 89CH₂-4-F—Ph 3-Indole d1,2 522^(C) 90 CH₂-4-F—Ph OCH₂Ph d1,2 513^(C) 91CH₂-3,4-di-F—Ph OCH₂-2,4-di-F—Ph d1,2 567^(C) 92 CH₂-3,4-di-F—Ph OCH₂Phd1,2 531^(C) 93 CH₂-3,5-di(CF₃)—Ph 3-indole d1,2 640^(C) 94CH₂-3,5-di(CF₃)—Ph OCH₂Ph d1,2 641^(C) 95 CH₂-3,5-di(CF₃)—PhOCH₂-2,4-di-F—Ph d1,2 667^(C)

EXAMPLES 96-97

[0989] The compounds of examples 96-97 were synthesized in a manneranalogous to the procedures described for Example 1, using theappropriate starting materials.

Ex. # R¹ R″ MS 96 CH₂-4-(CF₃)Ph 1-Naphthalene 609^(C) 97 CH₂-4-F—Ph1-Naphthalene 559^(C)

EXAMPLES 98-150

[0990] The compounds of examples 98-150 were synthesized in a manneranalogous to the procedures described for Example 9, using theappropriate starting materials.

Ex. # R² R¹ R″ isomer MS  98 H CH₂Ph OCH₂Ph d2 510  99 H CH₂Ph OCH₂Ph d1495 100 H CH₂Ph OCH₂Ph d3 495 101 H CH₂Ph 3-Indole d1 504^(C) 102 MeCH₂Ph 3-Indole d1 518^(C) 103 H CH₂Ph 3-Indole d3 503^(C) 104 Me CH₂Ph3-Indole d3 517^(C) 105 H H OCH₂Ph d1,2 405^(C) 106 H CH₂Ph3-(N—Me)Indole d2 518^(C) 107 H CH₂Ph OCH₂-2-Pyr d2 496^(C) 108 H CH₂Ph5-Thiazole d3 502^(C) 109 H CH₂Ph SCH₂Ph d3 511^(C) 110 H CH₂-4-PyrOCH₂Ph d1,2,3,4 496^(C) 111 H CH₂Ph SCH₂Ph d2 511^(C) 112 Me CH₂-4-PyrOCH₂Ph d1 510^(B) 113 Me CH₂-4-Pyr OCH₂Ph d2 510^(B) 114 H CH₂-3-PyrOCH₂Ph d1,2 496^(B) 115 H CH₂-3-Pyr OCH₂Ph d3,4 496^(B) 116 H CH₂-2-PyrOCH₂Ph d2 496^(C) 117 H CH₂-2-Pyr OCH₂Ph d3 496^(C) 118 Me CH₂-4-PyrOCH₂Ph d3 510^(B) 119 Me CH₂-4-Pyr OCH₂Ph d4 510^(B) 120 Me CH₂-4-PyrOCH₂-2-Pyr d1,2,3,4 511^(B) 121 Me CH₂-3-Pyr OCH₂Ph d1,2,3,4 510^(B) 122Me CH₂-3-Pyr OCH₂Ph d1,2,3,4 510^(B) 123 Me CH₂-3-Pyr OCH₂Ph d1,2,3,4510^(B) 124 Me CH₂-4-Pyr 3-Indole d1,2,3,4 519^(B) 125 H CH₂-4-Pyr3-Indole d1,2,3,4 505^(B) 126 H CH₂-5-Thiazole OCH₂Ph d1,2,3,4 502^(B)127 H CH₂CH₂Ph OCH₂Ph d1,2,3,4 523^(B) 128 Me CH₂CH₂Ph OCH₂Ph d1,2,3,4537^(B) 129 Me CH₂-3-Pyr OCH₂-2-CF₃—Ph d1,2 578^(B) 130 Me CH₂-3-PyrOCH₂-2-CF₃—Ph d3 578^(B) 131 Me CH₂-3-Pyr OCH₂-2-CF₃—Ph d4 578^(B) 132Me CH₂-2-Pyr OCH₂Ph d2 510^(C) 133 Me CH₂-2-Pyr OCH₂-2,4-di-F—Ph d2546^(C) 134 H CH₂-3-Pyr OCH₂-2,4-di-F—Ph d1,2 532^(C) 135 Me CH₂-3-PyrOCH₂-2,4-di-F—Ph d1,2 546^(C) 136 Me CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 544^(C)137 Et CH₂-3-Pyr OCH₂Ph d1,2 524^(C) 138 Et CH₂-3-Pyr OCH₂-2,4-di-F—Phd1,2 560^(C) 139 Et CH₂-3-Pyr OCH₂-4-Cl—Ph d1,2 558^(C) 140 CH₂Ph HOCH₂Ph d1,2 495^(C) 141 CH₂Ph H OCH₂-2-Pyr d1,2 496^(C) 142 CH₂-2-Pyr HOCH₂Ph d2 496^(C) 143 CH₂-2-Pyr H OCH₂Ph d1 496^(C) 144 CH₂-2-Pyr HOCH₂-2,4-di-F—Ph d2 532^(C) 145 CH₂-2-Pyr H OCH₂-2,4-di-F—Ph d1 532^(C)146 CH₂-2-Pyr H OCH₂-2-CF₃—Ph d2 564^(C) 147 CH₂-2-Pyr H OCH₂-2-CF₃—Phd1 564^(C) 148 H CH₂-3,5-di-Cl- OCH₂—Ph d1,2 564^(C) 4-Pyr 149 HCH₂-3,5-di-Cl- OCH₂—Ph d3,4 564^(C) 4-Pyr 150 CH₂-2-Pyr H OCH₂-2-Pyrd1,2 497^(C)

EXAMPLES 151-163

[0991] The compounds of examples 151-163 were synthesized in a manneranalogous to the procedures described for Example 11, using theappropriate starting materials.

Ex. # R² R¹ R″ MS 152 Me H OCH₂Ph 431^(B) 153 Me H 3-Indole 440^(B) 154H H 3-Indole 426^(B) 155 Me CH₂Ph OCH₂Ph 521^(B) 156 Me CH₂Ph 2-Indole530^(B) 157 Me CH₂Ph OCH₂-2-Pyr 522^(B) 158 Me CH₂-2-Pyr OCH₂Ph 522^(B)159 Me CH₂Ph OCH₂-2,4-di-F—Ph 557^(B) 160 Me CH₂-2-Pyr OCH₂-2,4-di-F—Ph558^(B) 161 Me CH₂Ph OCH₂-4-Thiazole 528^(B) 162 Me CH₂PhOCH₂-4-Thiazole 528^(B) 163 Me CH₂-2-Pyr OCH₂-2-(Me)Ph 536^(B)

EXAMPLES 164-171

[0992] The compounds of examples 164-171 were synthesized in a manneranalogous to the procedures described for Example 13, using theappropriate starting materials.

Ex. # R¹ R² R″ MS 164 Ph H OCH₂Ph 490^(B) 165 Et H OCH₂Ph 442^(B) 166 MeMe OCH₂Ph 442^(B) 167 Me Me 3-Indole 451^(B) 168 Et Me OCH₂Ph 456^(B)169 Et Me 3-Indole 465^(B) 170 Et CH₂Ph OCH₂Ph 532^(B) 171 Et CH₂Ph3-Indole 541^(C)

EXAMPLES 172-176

[0993] The compounds of examples 172-176 were synthesized in a manneranalogous to the procedures described for Example 7, using theappropriate starting materials.

Ex. # R² R¹ R″ MS 172 Me CH₂Ph OCH₂Ph 507^(C) 173 H CH₂Ph OCH₂Ph 493^(C)174 H CH₂Ph OCH₂-3-Pyr 494^(B) 175 H CH₂Ph OCH₂-2-Pyr 494^(B) 176 HCH₂Ph CH₂CH₂Ph 491^(C)

EXAMPLES 177-178

[0994] The compounds of examples 177-178 were synthesized in a manneranalogous to the procedures described for Example 8, using theappropriate starting matterials.

Ex. # R¹ R″ MS 177 CH₂Ph OCH₂Ph 494^(B) 178 CH₂Ph OCH₂-2-Pyr 495^(C)

EXAMPLE 179-187

[0995] The compounds of examples 179-187 were synthesized in a manneranalogous to the procedures described for Example 6, using theappropriate starting materials.

Ex. # R¹ X R″ isomer MS 179 CH₂-2-F—Ph O OCH₂Ph d2 525^(C) 180CH₂-2-F—Ph O OCH₂Ph d1 525^(C) 181 CH₂-4-F—Ph O OCH₂Ph d2 525^(C) 182CH₂-4-F—Ph O OCH₂Ph d1 525^(C) 183 CH₂-4-F—Ph O OCH₂-2,4-di-F—Ph d2561^(C) 184 CH₂-4-F—Ph O OCH₂-2,4-di-F—Ph d1 561^(C) 185 CH₂-4-F—Ph SOCH₂Ph d1,2 541^(C) 186 CH₂-2-Pyr O OCH₂-2,4-di-F—Ph d1,2 544^(C) 187CH₂-2-Pyr O OCH₂Ph d1,2 508^(C)

EXAMPLES 188-196

[0996] The compounds of examples 188-196 were synthesized by couplingthe HET portion to the dipeptidyl portion in a manner analogous to theprocedures described in General Procedure B or Example part 3a-B; theHET portion was synthesized in a manner analogous to the methodindicated, using the appropriate starting materials.

Method of Preparation Ex. # HET R″ of HET MS 188

3-Indole Scheme 57 474 (TSMS) 189

3-Indole Scheme 57 460^(B) 190

OCH₂Ph Scheme 35 521^(B) 191

OCH₂-2-Pyr Example 12 471^(B) 192

OCH₂Ph Scheme 58 529^(B) 193

OCH₂Ph Scheme 27 557^(C) 194

3-Indole Scheme 27 530^(C) 195

OCH₂Ph Scheme 56 525^(C) 196

OCH₂Ph Scheme 56 525^(C)

EXAMPLE 197

[0997]

[0998] A. 2-Formyl-2-pyridin-2-ylmethyl-piperazine-1,4-dicarboxylic acid1-benzyl ester 4-tert-butyl ester:

[0999] A solution of the ester of Example 3, Step A (1.4 g, 3 mmol) inCH₂Cl₂ (10 mL) was cooled to −50° C. and a 1.0 M solution of DIBAL inCH₂Cl₂ (18 mL, 18 mmol) was slowly added. Once the DIBAL addition wascomplete the solution was stirred at −50° C. for 1 h. The reaction wasquenched with MeOH (2 mL) and 1 N NaOH (25 mL) was added. The aldehydewas extracted with CH₂Cl₂ (3×25 mL). The extracts were combined, washedwith brine, dried over MgSO₄ and concentrated to give the aldehyde ofExample 197, Step A as a yellow oil (1.0 g, 76%) which was carried onwithout further purification: +APcl MS (M+1)⁺440, (M−^(t)Bu+1)⁺384,(M−Boc+1)⁺340; ¹H NMR=400 MHz (CDCl₃) δ: 9.51 (br s, 1H), 4.55 (m, 2H),1.38 (s, 9H).

[1000] B.2-(Hydroxyimino-methyl)-2-pyridin-2-ylmethyl-piperazine-1,4-dicarboxylicacid 1-benzyl ester 4-tert-butyl ester:

[1001] A solution of the aldehyde of Example 197, Step A (439 mg, 1mmol) and hydroxylamine hydrochloride (278 mg, 4 mmol) in pyridine (5mL) was stirred for 12 h at rt. Solvent was removed under reducedpressure and the resulting residue was dissolved into chloroform (20mL), washed with saturated NaHCO₃ and brine solutions, dried over MgSO₄and concentrated to give 462 mg of a crude yellow oil. Purification byflash chromatography (SiO₂ gel, 3:1 EtOAc:hexane) delivered 342 mg (75%)of the oxime of Example 197, Step B as a colorless oil: +APcl MS(M+1)⁺455, (M−^(t)Bu+1)⁺399, (M−Boc+1)⁺355; ¹H NMR=400 MHz (CDCl₃) δ:8.55 (m, 1H), 5.27 (m, 1H), 4.98 (m, 1H), 1.42 (s, 9H).

[1002] C.3-Oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-]pyrazine-7-carboxylicacid tert-butyl ester:

[1003] To a solution of the oxime of Example 197, Step B (342 mg, 0.75mmol) in EtOH (10 mL) was added Raney nickel (1 mL of a suspension inwater), followed by NaOH (150 mg, 3.75 mmol). The mixture was stirred atroom temperature for 2 h and filtered through Celite®. The filtrate wasconcentrated to afford the urea of Example 197, Step C as a white solid(534 mg, quantitative crude) which was carried on without furtherpurification: +APcl MS (M+1)⁺333, (M−^(t)Bu+1)⁺277, (M−Boc+1)⁺233.

[1004] D.{1-[1(R)-Benzyloxymethyl-2-oxo-2-(3-oxo8a(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[5-]pyrazin-7-yl)-ethylcarbamoyl]-1-methyl-ethyl}carbamicacid tert-butyl ester

[1005] To a solution of the crude urea of Example 197, Step C (534 mg)in EtOH (15 mL, 0° C.) was added conc. HCl (1.5 mL). The solution wasstirred at 0° C. for 1 h and concentrated down to provide thedeprotected piperazine as a viscous, colorless oil: +Apcl MS (M+1)⁺333.

[1006] The residue was dissolved into 15 m,L EtOAc and triethylamine(0.2 mL, 1.5 mmol) was added. After stirring for 15 min , the acid ofExample 2, Step I (380 mg, 1mmol), PPAA (0.32 mL, 1 mmol) andtriethylamine (0.4 mL, 4 mmol) were added and the mixture was stirred atroom temperature for 4 h. Water (20 ml) was added and the product wasextracted with EtOAc (3×25 mL). The combined extracts were washed withbrine, dried over MgSO₄ and concentrated to give 612 mg of a crudeyellow oil. Purification by flash chromatography (SiO₂ gel, 9:1EtOAc:EtOH) delivered 72 mg (16% yield from the oxime) of the compoundof Example 197, Step D as a 1:1 mixture of diastereomers: +APcl MS(M+1)⁺595, (M−Boc+1)⁺495; ¹H NMR=400 MHz (CDCl₃) δ: 8.47 (br m, 1H),5.18 (br m, 1H), 4.85 (br m, 1H), 1.45 (s, 0.5×3H), 1.44 (s, 0.5×3H),1.42 (br s, 3H) 1.39 (br s, 9H).

[1007] E.2-Amino-N-[1(R)-benzyloxymethyl-2-oxo-2-(3-oxo-8a(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-]pyrazin-7-yl)-ethyl]-2-methyl-propionamide,hydrochloride:

[1008] To a solution of the compound of Example 197,Step D (30 mg) inEtOH (5 mL), at 0° C. was added conc. HCl (0.5 mL). The solution wasstirred at 0° C. for 1 h and concentrated down to deliver 28 mg of thecompound of Example 197, Step E: +APcl MS (M+1)⁺495; ¹H NMR=400 MHz(CD₃OD) δ: 8.58 (br m, 1H), 4.58 (br m, 2H), 1.61 (brs, 6H).

EXAMPLE 198

[1009]

[1010] A. 3-(2,4-Difluoro-benzyl)-3-formyl-piperazine-1-carboxylic acidtert-butyl ester:

[1011] A solution of ester3-(2,4-difluoro-benzyl)-piperazine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester, prepared analogously to the compound of Example 2,Step A, (1.11 g, 3 mmol) in CH₂Cl₂ (10 mL) was cooled to −40° C. and a1.0 M solution of DIBAL in CH₂Cl₂ (9 mL, 9 mmol) was slowly added. Oncethe DIBAL addition was complete the solution was allowed to stir at −40°C. for 1 h. The reaction was quenched with MeOH (2 mL) and 1 N NaOH (25mL) was added. The aldehyde was extracted with CH₂Cl₂(3×20 mL). Theextracts were combined, washed with brine, dried over MgSO₄ andconcentrated to give the compound of Example 198, Step A as a yellow oil(647 mg, 64%) which was carried on without further purification: +APclMS (M+1)⁺341, (M−^(t)Bu+1)⁺285, (M−Boc+1)³⁰ 241; ¹H NMR=400 MHz (CDCl₃)δ: 9.60 (br s, 1H), 7.10 (m, 1H), 6.78 (m, 2H), 1.41 (s, 9H).

[1012] B.3-(2,4-Difluoro-benzyl)-3-methylaminomethyl-piperazine-1-carboxylic acidtert-butyl ester:

[1013] To a solution of the aldehyde of Example 198, Step A (340mg,1mmol) in dry DME (10 mL) was added about 250 mg MgSO₄ followed bymethyl amine (1 mL of a 2.0 M solution in MeOH, 2 equiv). The reactionwas monitored by MS for the consumption of aldehyde and formation of thecorresponding imine (+APcl (M+1)⁺354). Once imine formation wascomplete, NaOAc (820 mg, 10 mmol) and NaCNBH₃ (248 mg, 4 mmol) wereadded and the mixture was stirred at room temperature for 1 h. Themixture was filtered through Celite® and the filtrate was concentrated.The resulting residue was taken up in EtOAc (25 mL) and washed with 1 NNaOH and brine solutions, respectively. The organic phase was dried overMgSO₄ and concentrated to deliver the crude amine (306 mg). Purificationby flash chromatography (SiO₂ gel, 3:1:0.2 EtOAc:Hexane:EtOH) delivered210 mg (59%) of the diamine of Example 198, Step B: +APcl MS (M+1)⁺356,(M−^(t)Bu+1)⁺300, (M−Boc+1)⁺256; ¹H NMR=400 MHz (CDCl₃) δ: 7.21 (m, 1H),6.81 (m, 2H), 2.51 (br s, 3H), 1.42 (s, 9H).

[1014] C.8a-(2,4-Difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-]pyrazine-7-carboxvlicacid tert-butyl ester:

[1015] To a solution of the diamine of Example 198, Step B (178 mg, 0.5mmol) in CH₂Cl₂ (5 mL) was added triethylamine (0.13 mL, 1 mmol) andtriphosgene (148 mg, 0.5 mmol). The resulting solution was stirred atroom temperature for 1 h and then quenched with water (10 mL). The ureawas extracted with CH₂Cl₂, dried over MgSO₄ and concentrated to deliverthe crude product (187 mg). Purification by flash chromatography (SiO₂gel, 1:1, EtOAc:Hexane) delivered 156 mg (82%) of the urea of Example198, Step C: +APcl MS (M+1)⁺382, (M−^(t)Bu+1)⁺326, (M−Boc+1)⁺282.3; ¹HNMR=400 MHz (CDCl₃) δ: 7.24 (m, 1H), 6.81 (m, 2H), 2.67 (br s, 3H), 1.48(s, 9H).

[1016] D. (1-{1(R)-Benzyloxymethyl-2-[8a(S)-(2,4-difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-]pyrazin-7-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[1017] To a solution of the compound of Example 198, Step C (38 mg, 0.1mmol) in EtOH (2 mL) was added 0.5 mL of conc. HCl at 0° C. The solutionwas stirred for 1 h. Water (10 mL) was added and the resulting solutionwas basified to pH 14 with 1 N NaOH. The amine was extracted with CH₂Cl₂(3×10 mL) and the combined extracts were dried over MgSO₄ andconcentrated to deliver 27 mg of the urea: +APcl MS (M+1)⁺282. To asolution of the above urea (27 mg, 0.1 mmol) in EtOAc (5 mL) was addedtriethylamine (0.07 mL, 0.5 mmol), PPM (0.035 mL, 0.1 mmol) and the addof Example 2, Step I (38 mg, 0.1 mmol). The solution was stirred at roomtemperature for 3 h. Water (10 mL) was added and the product wasextracted with EtOAc (3×15 mL). The combined extracts were dried overMgSO₄ and concentrated to provide a pale yellow oil. Purification byflash chromatography (SiO₂ gel, 3:1, EtOAc:hexanes) delivered 12 mg(19%) of the compound of Example 198, Step D (less polar diastereomer):+APcl MS (M+1)⁺644, (M−Boc+1)⁺544; ¹H NMR=400 MHz (CDCl₃) δ: 7.26 (m,6H), 6.91 (m, 2H), 2.63 (s, 3H), 1.38 (s, 9H).

[1018] E.2-Amino-N-{1(R)-benzyloxymethyl-2-[8a(S)-(2,4-difluoro-benzyl)-2-methyl-3-oxo-hexahydro-imidazo[1,5-]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,hydrochloride

[1019] To a solution of the compound of Example 198, Step D (12 mg) inEtOH (2 mL, 0° C.) was added conc. HCl (0.2 mL). The solution wasstirred at 0° C. for 1 h and concentrated down to deliver 10 mg ofExample 198, Step E: +APcI MS (M+1)⁺544; ¹H NMR=400 MHz (CD₃OD) δ: 7.31(br m, 6H), 6.83 (m, 2H), 2.59 (br s, 3H), 1.56 (br s, 6H).

EXAMPLE 199

[1020]

[1021] A. 2(R)-Amino-5phenyl-pentanoic acid(2(S)-hydroxy-1(S)-methyl-2-phenyl-ethyl)-methyl-amide:

[1022] A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol),prepared and used by the method of Myers et al. (J. Am. Chem. Soc. 1997,119, 656), and LiClI (1.71 g, 40.5 mmol) in THF (30 mL) was cooled to−78° C and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution).After stirring for 20 min at −78° C., the reaction was warmed to 0° C.and stirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL,7.42 mmol) was added and the reaction was stirred for 2 h at 0° C.Aqueous 1 N HCl (50 mL) and EtOAc (50 mL) were added, the organic phasewas separated and extracted with 1 N HCl (50 mL). The aqueous extractswere combined, cooled in an ice bath and slowly basified to pH 14 with 6N NaOH. The product was extracted with CH₂Cl₂ (4×50 mL) and the combinedextracts were dried over MgSO₄ and concentrated to give a yellow oil.Purification by flash chromatography (SiO₂ gel, 92:4:4,CH₂Cl₂:MeOH:triethylamine) delivered 400 mg (78%) of the Product ofExample 199, Step A: +APcl MS (M+1)⁺341; ¹H NMR=400 MHz (CDCl₃) δ: 7.38(m, 10H), 5.26 (m, 1H), 4.15 (m, IH), 3.86 (m, 1H), 2.36 (s, 3H).

[1023] B. 2(R)-Amino-5-phenyl-pentanoic acid:

[1024] A solution of the compound of Example 199, Step A (400 mg, 1.18mmol) in water (10 mL) was heated to reflux for 20 h. The reaction wasdiluted with water (20 mL) and extracted with CH₂Cl₂ (2×20 mL). Thecombined organic extracts were back extracted with water (2×20 mL) andthe combined aqueous extracts were concentrated down to a white solid.The solid was triturated with EtOH to remove residual pseudoephedrineand deliver Example 199, Step B (135 mg, 60%): +APcl MS (M+1)⁺194.

[1025] C.2(R)-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-5-phenyl-pentanoicacid:

[1026] To a solution of the compound of Example 199, Step B (130 mg,0.67 mmol) in dioxane: water (4:1, 5 mL) was added triethylamine (0.28mL, 2 mmol) and Example 1, Step D (201 mg, 0.67 mmol). The mixture wasstirred at 45° C. for 16 h, diluted with EtOAc (20 mL) and water (10 mL)and acidified to pH 2 with HOAc. The organic phase was collected, washedwith saturated NaHCO₃ and brine solutions, dried over MgSO₄ andconcentrated to quantitatively give crude Example 199, Step C (298 mg):+APcl MS (M+1)⁺379, (M−^(t)Bu+1)⁺323, (M−Boc+1)+279; ¹H NMR=400 MHz(CDCl₃) δ: 7.21 (m, 2H), 7.14 (m, 3H), 4.51(m, 1H), 1.38 (s, 9H).

[1027] D.(1-{1(R)-[1,3-Dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-]pyrazine-7-carbonyl]-4-phenyl-butylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

[1028] To a solution of the hydantoin of the Example 3a, Step A (164 mg,0.5 mmol) in EtOAc (5 mL) was added triethylamine (0.35 mL, 2.5 mmol),PPAA (0.16 mL, 0.5 mmol) and 16-C (189 mg, 0.5mmol). The solution wasstirred at room temperature for 2 h. Water (10 mL) was added and theproduct was extracted with EtOAc (3×15 mL). The combined extracts weredried over MgSO₄ and concentrated to provide 382 mg of a pale yellowoil. Purification by flash chromatography (SiO₂ gel, 3:1, EtOAc:hexanes)delivered 73 mg of the compound of Example 199, Step D(diastereomerically pure): +APcl MS (M+1)⁺689, (M−^(t)Bu+1)⁺633,(M−Boc+1)⁺589; ¹H NMR=400 MHz (CDCl₃) δ: 8.37 (m, 1H), 4.90 (br m, 3H),1.50 (s, 3H), 1.48 (s, 3H),1.38 (s, 9H).

[1029] E.2-Amino-N-{1(R)-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-]pyrazine-7-carbonyl]-4-phenyl-butyl}-2-methyl-propionamidehydrochloride:

[1030] To a solution of the compound of Example 199, Step D (73 mg) inEtOH (5 mL, 0° C.) was added conc. HCl (0.5 mL). The solution wasstirred at 0° C. for 1 h and concentrated down to deliver 68 mg ofExample 199, Step E: +APcl MS (M+1)⁺589; ¹H NMR=400 MHz (CD₃OD) δ: 8.36(d, 1H), 4.86 (br m, 3H), 1.44 (s, 3H), 1.42 (s, 3H).

EXAMPLE 200

[1031]

[1032] A. 1,3-Dibenzyl-4-oxo-piperdine-3-carboxylic acid methyl ester:

[1033] To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acidmethyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was addedsodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) infour portions over 0.5 h. After stiming at 0° C. for an additional 0.5h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reactionmixture was allowed to stir for 14 h while warming to room temperature.The reaction mixture was partitioned between EtOAc and saturated aqueoussodium bicarbonate solution, the organic layer was removed and theaqueous layer was washed four times with EtOAc. The combined organiclayers were dried over sodium sulfate, filtered and concentrated undervacuum. Purification by silica gel chromatography employing 0.5%MeOH/0.2% NH₄OH/CH₂Cl₂ as the eluant afforded the compound of Example200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)⁺338; ¹H NMR(400 MHz, CDCl₃) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H),3.56 (d, 2H), 3.38 (m, ₁H), 3.20 (d, ₁H), 2.93 (m, 2H), 2.78 (m, 1H),2.42 (m, 2H), 2.31 (m, 1H).

[1034] B. 1,3-Dibenzyl-4-methoxymethylene-piperidine-3-carboxylic acidmethyl ester:

[1035] The material was prepared from the compound of Example 200, StepA (3.56 g, 11.0 mmol) as described in Example 8, Step A, affording thecompound of Example 200, Step B as a pale yellow oil after purificationvia silica gel chromatography with 2-8% EtOAc/CH₂Cl₂ as the eluant (4.02g): +APcl MS (M+1)⁺366; ¹H NMR (400 MHz, CDCl₃) d: 7.08-7.35 (arom,series of m, 10 H), 5.94 (s, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.05 (d,1H).

[1036] C. 1,3-Dibenzyl-4-formyl-piperidine-3-carboxylic acid methylester:

[1037] A solution of the compound of Example 200, Step B (3.02 g, 8.26mmol) in THF (40 mL) and 10% aqueous HCl solution (40 mL) was allowed tostir at room temperature for 14 h. The solution was adjusted to pH 9with 5N NaOH and extracted twice with CH₂Cl₂. The combined organiclayers were washed with a saturated aqueous brine solution, dried overNa₂SO₄, filtered and concentrated under vacuum. Purification by silicagel chromatography employing 3-5% EtOActCH₂CI₂ as the eluant affordedthe compound of Example 200, Step C as a mixture of isomers (1.89 g):+APcl MS (M+1)⁺352; ¹H NMR (400 MHz, CDCl₃) δ: 9.82 and 9.81 (s, 1H),7.02-7.45 (arom, series of m, 10 H), 3.64 and 3.60 (s, 3H).

[1038] D. 3a,5-Dibenzyl-2-methyl-octahydro-pyrrolo[3,4-]pyridin-3-one:

[1039] To a solution of the compound of Example 200, Step C (0.210 g,0.60 mmol) in dichloroethane (5 mL) in a resealable tube was addedacetic acid (0.188 mL, 3.28 mmol), methyl amine (2.0 M in MeOH, 1.64 mL,3.28 mmol) and NaB(OAc)₃H (0.951 g, 4.48 mmol), the tube was sealed andthe reaction mixture was heated to 70° C. for 30 h. The reaction mixturewas partitioned between CH₂Cl₂ and saturated aqueous sodium bicarbonatesolution. The organic layer was removed and the aqueous layer was washedtwice with CH₂Cl₂, the combined organic layers were washed with asaturated aqueous brine solution, dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by silica gel chromatographyemploying 5-20% EtOAc/CH₂Cl₂ as the eluant afforded the less polarisomer of Example 200, Step D (0.034 g) as well as the more polar isomer(0.046 g). Example 200, Step D less polar isomer: +APcl MS (M+1)⁺335; ¹HNMR (400 MHz, CDCl₃) δ: 7.03-7.37 (arom, series of m, 10H), 3.54 (m,2H), 3.24 (m, 1H), 2.70 (s, 3H). More polar isomer: +APcl MS (M+1)⁺335;¹H NMR (400 MHz, CDCl₃) 67 : 7.15-7.33 (arom, series of m, 10 H), 3.59(d, 1H), 3.43 (d, 1H), 2.74 (s, 3H).

[1040] E. 3a-Benzyl-2-methyl-octahydro-pyrrolo[3,4-]pyridin-3-one:

[1041] To a solution of the compound of Example 200, Step D (0.034 g,0.10 mmol) in acetic acid (18 mL) was added a slurry of palladium oncarbon (10% by weight, 0.030 g) in H₂O (2 mL). The reaction mixture wasshaken under 50 psig hydrogen for 24 h, an additional aliquot ofpalladium on carbon (0.030 g) was introduced and the reaction wascontinued under 50 psig hydrogen for another 24 h. The reaction mixturewas filtered through a bed of Celite® with the aid of MeOH, concentratedunder vacuum, and the residue was partitioned between CH₂Cl₂ and H₂O atpH 9. The organic layer was removed and the aqueous layer was washedtwice with CH₂Cl₂, the organic layers were combined and washed with asaturated aqueous brine solution, dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by silica gel chromatographyemploying 3% MeOH/0.2% NH₄OH/CH₂Cl₂ as the eluant afforded the compoundof Example 200, Step E (0.019 g): +APcl MS (M+1)⁺245; ¹H NMR (400 MHz,CDCl₃) δ: 7.10-7.24 (arom, series of m, 5 H), 3.21 (m, 1H), 2.71 (s,3H).

[1042] F.{1-2-(7a(R)-3a(S)-Benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl-]1-methyl-ethyl}-carbamicacid tert-butyl ester:

[1043] To a solution of the compound of Example 200, Step E (0.019 g,0.078 mmol), the acid of Example 2, Step 1 (0.045 g, 0.12 mmol) and Et₃N(0.045 mL, 0.31 mmol) in EtOAc (1 mL) at 0° C. was added PPAA (50%solution in EtOAc, 0.093 mL, 0.16 mmol). After 24 h of stirring at roomtemperature, additional 2-I (0.015 g, 0.039 mmol) and PPAA (0.045 mL,0.078 mmol) were added and stirring was continued at room temperaturefor 24 h. The reaction mixture was partitioned between EtOAc andsaturated aqueous sodium bicarbonate solution, the organic layer wasremoved and the aqueous layer was washed twice with EtOAc. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under vacuum. Purification by silica gelchromatography employing EtOAc as the eluant afforded the less polarisomer of Example 200, Step F (0.005 g), as well as a mixture of the twoisomers (0.028 g). Example 200, Step F less polar isomer: +APcl MS(M+1)⁺607; ¹H NMR (400 MHz, CDCl₃) δ: 7.03-7.32 (arom, series of m, 10H), 5.27 (m, 1H), 4.48 (m, 2H), 2.69 (s, 3H), 1.35 (s, 9H).

[1044] G.2-Amino-N-[2-(7a(R)-3a(S)-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4-]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,hydrochloride: The compound of Example 200, Step F (0.005 g, 0.009 mmol)was deprotected as described in General Procedure C to provide thecompound of Example 200, Step G as the HCI salt (0.004 g). Example 200,Step G: +APcl MS (M+1)⁺507; ¹H NMR (400 MHz, CD₃OD) δ: 7.10-7.32 (arom,series of m, 10H), 5.23 (m, 1H), 2.73 (s, 3H), 1.56 (m, 6H).

EXAMPLE 201

[1045]

[1046] A. 3-Benzyl-3-(2-methoxycarbonyl-vinyl)-piperazine-1-carboxylicacid tert-butyl ester:

[1047] To a THF (1 mL) solution of NaHMDS at 0° C. was added trimethylphosphonoacetate (0.18 mL, 1.1 mmol), dropwise. After stirring for 1hour, a THF (1 mL) solution of crude3-benzyl-3-formyl-piperazine-1-carboxylic acid tert-butyl ester (0.34mg, 0.92 mmol), prepared analogous to the compound of Example 198, StepA, was added and the reaction was allowed to warm to room temperature.After stirring for 16 hours, the product was isolated by extraction fromwater with EtOAc (2×) and methylene chloride (2×). The combined extractswere washed with brine, dried (MgSO₄) and concentrated. The product wasthen purified by silica gel chromatography using methylene chloride,then 5% MeOH in methylene chloride as eluents to afford a 7:3 E:Zmixture of olefins of the compound of Example 201, Step A (0.38 g, 81%),where the Z isomer had lactamized: +APcl MS (M+1, ester)⁺361,(M−^(t)Bu+1, ester)⁺305, (M−^(t)Bu+1, lactam)⁺273, (M-BOC+1, ester)⁺261,(M−BOC+1, lactam)⁺229; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom,series of m, 5 H), 6.91 (lactam olefin, d, 0.3H), 6.75 (ester olefin, d,0.7H), 6.09 (lactam olefin, d, 0.3H), 5.88 (ester olefin, d, 0.7H), 3.71(ester Me, s, 2.1H), 1.47 (BOC, s, 9H).

[1048] B. 3-Benzyl-3-(2-methoxycarbonyl-ethyl)-piperazine-1-carboxylicacid tert-butyl ester

[1049] A methanolic solution of the compound of Example 201, Step A washydrogenated (40 psi) in a Parr shaker over 10% Pd-C (35 mg). After 17hours, the reaction was filtered through a pad of Celite® and thenconcentrated to give yellowish solid of the compound of the compound ofExample 201, Step B (153 mg, 90%) which was a 1:2 mixture of ester andlactam: +APcl MS (M+1, ester)⁺363, (M+1, lactam)⁺331; ¹H NMR (400 MHz,CDCl₃) δ: 7.25-7.05 (arom, series of m, 5 H), 3.54 (ester Me, s, 1H),1.44 (lactam BOC, s, 6H), 1.37 (ester BOC, s, 3H).

[1050] C. 8a-Benzyl-6-oxo-hexahydro-pyrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester:

[1051] To a methanolic (4 mL) solution of the compound of Example 201,Step B was added solid K₂CO₃. The mixture was refluxed for 30 minutes,then concentrated and extracted from saturated aqueous NH₄Cl withmethylene chloride to give lactam of Example 201, Step C as a yellowishsolid (70.6 mg, 50%): +APcl MS (M+1)⁺331, (M−^(t)Bu+1)⁺275,(M−BOC+1)⁺231; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom, series of m,5 H), 4.06 (d, 1H) , 3.06 (d, 1H), 2.67 (d, 1H), 2.07 (m, 2H), 1.49(BOC, s, 6H).

[1052] D.8a(S*)-Benzyl-7(S*)-methyl-6oxo-hexahydro-pyrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester

[1053] To a THF (0.4 mL) solution of lithium diisopropylamide (2.0 mmol)at −78° C. was added the compound of Example 201, Step C (192 mg, 0.58mmol) in 1,2-dimethoxyethane (3 mL). After 20 minutes, methyl iodide(0.36 mL, 5.8 mmol) was added dropwise and the reaction was stirred anadditional 1 hour. The reaction was quenched at −78° C. with brine, andthe reaction was then extracted with EtOAc (3×), dried (MgSO₄), andconcentrated. The product was then purified by silica gel chromatographyusing 7:3 to 1:1 hexanes/EtOAc as eluents to afford the dimethyl lactam(78 mg, 37%),8a-benzyl-7,7-dimethyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester, the (R*,S*) methyl lactam (68 mg, 34%), followedby the (S*,S*) methyl lactam of Example 201, Step D (58 mg, 29%).Dimethyl lactam: +APcl MS (M+1)⁺359, (M−^(t)Bu+1)⁺303, (M−BOC+1)⁺259; ¹HNMR (400 MHz, CDCl₃) δ: 7.30-7.10 (arom, series of m, 5 H), 3.18 (td,1H), 3.0 (d, 1H), 2.0 (d, 1H), 1.49 (BOC, s, 9H), 1.13 (Me, s, 3H), 0.66(Me, br s, 3H). (R*,S*) lactam: +APcl MS (M+1)⁺345, (M−^(t)Bu+1)⁺289,(M−BOC+1)+245; ¹H NMR (400 MHz, CDCl₃) δ: 7.30-7.05 (arom, series of m,5 H), 3.04 (d, 1H), 2.66 (d, 1H), 2.31 (dd, 1H), 1.49 (BOC, s, 9H), 1.99(Me, d, 3H). The (S*, S*) lactam of Example 201, Step D: +APcl MS(M+1)⁺345, (M−^(t)Bu+1)⁺289, (M-BOC+1)+245; ¹H NMR (400 MHz, CDCl₃) δ:7.30-7.05 (arom, series of m, 5 H), 2.97 (d, 1H), 2.81 (d, 1H), 2.40 (m,1H), 1.48 (BOC, s, 9H), 0.73 (Me, br s, 3H).

[1054] E.{1-[2-(8a(S*)-Benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-]pyrazin-2-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}carbamicacid tert-butyl ester:

[1055] The compound of Example 201, Step D (58 mg, 0.17 mmol) wasdeprotected as described in General Procedure C to provide the secondaryamine as the HCl salt: +APcl MS (M+1)⁺245; ¹H NMR (400 MHz, CD₃OD) d:7.15-7.35 (arom, series of m, 5H), 4.26 (dd, 1H), 3.17 (d, 1H), 2.78 (d,1H) , 2.02 (dd, 1H), 1.76 (dd, 1H), 0.46 (Me, d, 3H).

[1056] To a solution of the crude amine, the acid of Example 2, Step 1(96 mg, 0.25 mmol) and Et₃N (0.16 mL, 1.2 mmol) in EtOAc (1 mL) at 0° C.was added PPAA (50% solution in EtOAc, 0.16 mL, 0.27 mmol). After 16 hof stirring at room temperature, the reaction mixture was extracted fromsaturated aqueous sodium bicarbonate with EtOAc, and the combinedextracts dried (MgSO₄) and concentrated. Purification by silica gelchromatography employing 7:3 EtOAc/hexanes, then EtOAc, then 19:1EtOAc/MeOH as eluants afforded the less polar isomer of Example 201,Step E (29 mg, 28%), the more polar isomer (41 mg, 40%), as well as somemixed fractions. Less polar isomer of Example 201, Step E: +APcl MS(M+1)⁺607, (M−BOC+1)⁺507; ¹H NMR (400 MHz, CDCl₃) δ: 7.35-6.80 (arom,series of m, 10 H), 4.68 (d, 1H), 4.47 (AB_(q), 2H), 2.63 (d, 1H), 0.91(Me, m, 1.5H), 0.63 (Me, d, 1.5H). More polar isomer +APcl MS (M+1)⁺607,(M−BOC+1)⁺507; ¹H NMR (400 MHz, CDCl₃) δ: 7.70-6.85 (arom, series of m,10 H), 4.65 (d, 1H), 4.50 (½Ab_(q), 1H), 4.41 (½Ab_(q), 1H), 2.86 (d,1H), 2.59 (d, 1H), 0.87 (Me, m, 1.5H), 0.63 (Me, d, 1.5H).

[1057] F. 2-Amino-N-[2-(8a(S*)-benzyl-7(S*)-methyl-6-oxo-hexahydro-pyrrolo[1,2-]pyrazin-2-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide:

[1058] The compound of Example 201, Step E (29 mg, 0.048 mmol) wasdeprotected as described in General Procedure C to provide, aftertrituration with ether, the compound of Example 201, Step F as its HClsalt (23 mg, 88%): +APcl MS (M+1)⁺507; ¹H NMR (400 MHz, CD₃OD) δ:7.40-6.90 (arom, series of m, 10H), 4.59 (d, 1H), 4.54 (s, 2H), 4.04 (d,1H), 2.71 (d, 1H), 2.57 (d, 1H).

EXAMPLE 202

[1059]

[1060] A.8-Hydroxy-6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrol[1,2-]pyrazine-2-carboxylicacid tert-butyl ester.

[1061] To a 0° C. methanolic (5 mL) solution of6,8-dioxo-8a-pyridin-2ylmethyl-hexahydro-pyrrol[(1,2-a]pyrazine-2-carboxylicacid tert-butyl ester (203 mg, 0.59 mmol), prepared analogously to thecompound of Example 6, Step D but used crude, small portions of sodiumborohydride were added until TLC indicated starting material wasconsumed.The reaction was then quenched with water, and then extractedfrom saturated aqueous NaHCO₃ with EtOAc. The combined extracts werewashed with brine, dried (MgSO₄), and concentrated. Purification bysilica gel-chromatography employing 3:7 then 2:1 EtOAc/hexanes aseluants afforded the alcohol of Example 202, Step A (95 mg, 38%): +APclMS (M+1)⁺348, (M+Bu+1)⁺292; ¹H NMR (400 MHz, CDCl₃) δ: 8.45 (arom, d,1H), 7.70-7.07 (arom, series of m, 3H), 4.00, (dd, 1H), 3.28 (AB_(q),2H), 2.64 (dd, 1H), 1.40 (BOC, s, 9H).

[1062] B.6-Oxo-8a-pyridin-2-ylmethyl-3,4,6,8a-tetrahydro-1H-pyrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester:

[1063] To a solution of the compound of Example 202, Step A (240 mg,0.69 mmol) and triethylamine (0.29 mL, 2.1 mmol) at 0° C. in methylenechloride (10 mL) was added methanesulfonyl chloride (0.11 mL, 1.4 mmol),dropwise. After stirring 18 hours, the sovent was removed under vacuumand was replaced with toluene (15 mL),1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 3.3 mmol) was added, and thereaction was heated for 4 hours at 100° C. The material was extractedfrom water with EtOAc, and the combined extracts were dried (MgSO₄) andconcentrated. Purification by silica gel chromatography employingchloroform then 19:1 chloroform/MeOH as eluants afforded the compound ofExample 202, Step B (147 mg, 65%): +APcl MS (M+1)⁺330, (M−^(t)Bu+l)⁺274;¹H NMR (400 MHz, CDCl₃) δ: 8.43 (arom, d, 1H), 7.55-6.90 (series of m,4H), 6.00, (olefin, d, 1H), 3.09 (d, 1H), 1.42 (BOC, s, 9H).

[1064] C.6-Oxo-8a-pyridin-2-ylmethyl-hexahydro-pvrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester:

[1065] To a −78° C. solution of the compound of Example 202, Step B inTHF (15 mL) was added lithium tri-sec-butylborohydride (1 M in THF, 1.44mL), the reaction was stirred 10 minutes and then allowed to warm toroom temperature. After 4 hours, the reaction was extracted fromsaturated aqueous NaHCO₃ with EtOAc. The combined extracts were washedwith brine, dried (MgSO₄), and concentrated to afford the compound ofExample 202, Step C (320 mg, quantitative): +APcl MS (M+1)+332,(M−^(t)Bu+1)⁺276; ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (arom, m, 1H), 7.55(arom, m, 1H), 7.15-7.00 (series of m, 2H), 3.99 (brd, 1H), 2.85 (d,1H), 1.43 (BOC, s, 9H).

[1066] D. 8a-Pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-]pyrazin-6-one:

[1067] The compound of Example 202, Step C (11 mg, 0.033 mmol) wasdeprotected as described in General Procedure C to provide the secondaryamine of Example 202, Step D as the HCl salt (9 mg, quantitative): +APclMS (M+1)⁺232; ¹H NMR (400 MHz, CD₃OD) δ: 8.87 (arom, d, 1H), 8.59 (arom,t, 1H), 8.06 (arom, t, 1H), 7.96 (arom, d, 1H), 4.32 (dd, 1H), 3.94 (d,1H), 3.74 (d, 1H), 1.59 (m, 1H).

[1068] E.{1-[1(R)-Benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyrdin-2-ylmethyl-hexahydro-pyrrolo[1,2-]pyrazin-2-yl)-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester:

[1069] To a solution of the compound of Example 202, Step D (330 mg,1.54 mmol), the acid of Example 2, Step 1(785 mg, 2.1 mmol) and EtN (1.1mL, 7.7 mmol) in EtOAc (10 mL) at 0° C. was added PPAA (50% solution inEtOAc, 0.88 mL, 2.10 mmol). After 2 h, the reaction mixture wasextracted from saturated aqueous sodium bicarbonate with EtOAc, and thecombined extracts washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography employing EtOAc, then 19:1EtOAc/MeOH as eluants afforded the compound of Example 202, Step E (250mg, 29%) as a 1:1 mixture of diasteremers: +APcl MS (M+1)⁺594,(M−BOC+1)⁺494.

[1070] F.2-Amino-[-1(R)-benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-]pyrazin-2-yl)-ethyl]-2-methyl-propionamide:

[1071] Compound of Example 202, Step E (12 mg, 0.020 mmol) wasdeprotected as described in General Procedure C to provide, aftertrituration with ether, Example 202, Step F as its HCl salt (5 mg, 50%):+APcl MS (M+1)+494; ¹H NMR (400 MHz, CD₃OD) δ: 8.90-7.15 (arom, seriesof m, 9H), 5.31 (m, 0.5H), 5.15 (m, 0.5H), 2.86 (d, 0.5H), 2.77 (d,0.5H), 1.60 (Me, m, 6H).

EXAMPLE 203

[1072]

[1073] A.8a-(4-Fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-]pyrazine-2-carboxylicacid tert-butyl ester:

[1074] To a DMSO (2 mL) solution of the compound of Example 6, Step Dwas added NaH (60% dispersion in mineral oil, 33 mg, 0.83 mmol) wasadded methyl iodide (0.017 mL, 0.28 mmol), the mixture was stirred for 1hour, and then an additional portion of methyl iodide (0.017 mL, 0.28mmol) was added. After stirring 3 days, the reaction mixture wasextracted from saturated aqueous sodium bicarbonate with EtOAc, and thecombined extracts washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography employing hexanes, then 1:1EtOAc/hexanes as eluants afforded the compound of Example 203, Step A(20 mg, 29%): +APcl MS (M−^(t)Bu+1)⁺335, (M−BOC+1)⁺291; ¹H NMR (400 MHz,CDCl₃) δ: 6.93 (arom, m, 4 H), 4.40 (dd, 1H), 1.50 (BOC, s, 9H), 1.13(Me, s, 3H), 0.26 (Me, s, 3H).

[1075] B.8a-(4-Fluoro-benzyl)-7,7-dimethyl-tetrahydro-pyrrolo[1,2-]pyrazine-6,8-dione:

[1076] The compound of Example 203, Step A (20 mg, 0.061 mmol) wasdeprotected as described in General Procedure C to provide the secondaryamine of Example 203, Step B as the HCl salt (17 mg, 85%): +APcl MS(M+1)⁺291; ¹H NMR (400 MHz, CD₃OD) δ: 7.04 (arom, m, 4H), 4.56 (dd, 1H),3.50 (d, 1H), 3.07 (d, 1H), 1.16 (Me, s, 3H), 0.16 (Me, s, 3H).

[1077] C.[1-{1f(R)-Benzyloxymethyl-2-[8a(S)-(4-fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-]pyrazin-2-yl]-2-oxo-ethylcarbamoyl}-methyl-ethyl)-carbamicacid tert-butyl ester:

[1078] To a solution of the compound of Example 203, Step B (17 mg,0.052 mmol), the acid of Example 2, Step 1(24 mg, 0.062 mmol) and Et₃N(0.036 mL, 0.26 mmol) in EtOAc (0.5 mL) at 0° C. was added PPAA (50%solution in EtOAc, 0.88 mL, 2.10 mmol). After 3 h, the reaction mixturewas extracted from saturated aqueous sodium bicarbonate with EtOAc, andthe combined extracts washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography employing hexanes, then 1:1EtOAc/hexanes as eluants afforded the less polar isomer of Example 263,Step C (4 mg, 28%) followed by the more polar isomer (6 mg, 43%). Lesspolar isomer of Example 203, Step C: +APcl MS (M−BOC+1)⁺553; ¹H NMR (400MHz, CDCl₃) δ: 7.40-6.80 (arom, series of m, 9H), 4.85 (d, 1H), 4.47(Ab_(q), 2H), 2.51 (d, 1H), 1.12 (Me, s, 3H), 0.24 (Me, s, 3H). Morepolar isomer: +APcl MS (M−BOC+1)⁺553; ¹H NMR (400 MHz, CDCl₃) δ:7.35-6.50 (arom, series of m, 9H), 4.85 (d, 1H) , 4.55 (½Ab_(q), 1H),4.42 (½Ab_(q), 1H), 2.87 (d, 1H), 2.45 (d, 1H), 1.08 (Me, s, 3H), 0.15(Me, s, 3H).

[1079] D.2-Amino-N{1(R)-benzyloxvmethyl-2-[8a(S)-(4-fluoro-benzyl)-7,7-dimethyl-6,8-dioxo-hexahydro-pyrrolo[1,2-]pyrazin-2-yl]-2-oxo-ethyll2-methyl-propionamide:

[1080] The compound of Example 203, Step C (4 mg, 0.006 mmol) wasdeprotected as described in General Procedure C to provide, aftertrituration with ether, the compound of Example 201, Step F as its HClsalt (3 mg, 83%): +APcl MS (M+1)⁺553; ¹H NMR (400 MHz, CD₃OD) δ:7.40-6.90 (arom, series of m, 9 H), 5.16 (t, 1H), 4.69 (d, 1H), 4.54 (s,2H), 2.85 (t, 1H), 1.56 (ala Me, s, 6H), 1.12 (Me, s, 3H), 0.20 (Me, s,3H).

[1081] The following abbreviations and notations are used in the Tablesbelow.

[1082] Abbreviation:

[1083] Me—methyl

[1084] Et—ethyl

[1085] Ph—phenyl

[1086] Pyr—pyridyl

[1087] c-Pr—cyclopropyl

[1088] A=Mass Spec. Method is ⁻AP_(c)l

[1089] B=Mass Spec. Method is PB

[1090] C=Mass Spec. Method is ⁺AP_(c)l

EXAMPLES 204-206

[1091] The compounds of examples 204-206 were synthesized in a manneranalogous to the procedures described for Example 9 using theappropriate starting materials.

Example R² R¹ R″ isomer MS 204 Me CH₂-2-Pyr OCH₂Ph d1,2 510^(c) 205 EtCH₂-w-Pyr OCH₂Ph d1,2 524^(c) 206 Et CH₂-2-Pyr OCH₂Ph d3,4 524^(c)

EXAMPLES 207-230

[1092] The compounds of examples 207-230 were synthesized in a manneranalogous to procedures described for Example 200 using the appropriatestarting materials.

Example R² R¹ R″ isomer MS 207 Me CH₂Ph OCH₂Ph d1 507^(C) 208 Me CH₂PhOCH₂Ph d2 507^(C) 209 Me CH₂Ph OCH₂Ph d4 507^(C) 210 Me CH₂Ph OCH₂Phd3,4 507^(C) 211 c-Pr CH₂Ph OCH₂Ph d1,2 533^(C) 212 c-Pr CH₂Ph OCH₂Ph d3533^(C) 213 c-Pr CH₂Ph OCH₂Ph d3,4 533^(C) 214 Et CH₂Ph OCH₂Ph d1,2521^(C) 215 Et CH₂Ph OCH₂Ph d3,4 521^(C) 216 Me CH₂-4-F—Ph OCH₂Ph d3,4525^(C) 217 Me CH₂-4-F—Ph OCH₂Ph d1,2 525^(C) 218 CF₃CH₂ CH₂Ph OCH₂Ph d3575^(C) 219 CF₃CH₂ CH₂-4-F—Ph OCH₂Ph d3,4 593^(C) 220 CF₃CH₂ CH₂PhOCH₂Ph d4 575^(C) 221 CF₃CH₂ CH₂-4-F—Ph OCH₂Ph d1,2 593^(C) 222 CF₃CH₂CH₂Ph OCH₂Ph d1,2 575^(C) 223 Et CH₂-4-F—Ph OCH₂Ph d1,2 539^(C) 224 EtCH₂-4-F—Ph OCH₂Ph d3 539^(C) 225 Et CH₂-4-F—Ph OCH₂Ph d4 539^(C) 226 BnCH₂-4-F—Ph OCH₂Ph d1,2,3,4 601^(C) 227 Me CH₂-2-Pyr OCH₂Ph d1,2 508^(C)228 Et CH₂-2-Pyr OCH₂Ph d1,2 522^(C) 229 H CH₂Ph OCH₂Ph d1,2 493^(C) 230H CH₂Ph OCH₂Ph d3,4 493^(C)

EXAMPLE 231

[1093] The compound of Example 231 was synthesized in a manner analogousto procedures described for Example 203 using the appropriate startingmaterials.

Example R² R¹ R″ isomer MS 231 Me CH₂-2-F—Ph OCH₂Ph d2 553^(C)

EXAMPLES 232-238

[1094] The compounds of examples 232-238 were synthesized in a manneranalogous to procedures described for Examples 201 and 202 using theappropriate starting materials.

Example R² R³ R¹ R″ isomer MS 232 H H CH₂Ph OCH₂Ph d1 493^(C) 233 H HCH₂Ph OCH₂Ph d2 493^(C) 234 H Me CH₂Ph OCH₂Ph d2 507^(C) 235 H Me CH₂PhOCH₂Ph d3 507^(C) 236 H Me CH₂Ph OCH₂Ph d4 507^(C) 237 Me Me CH₂PhOCH₂Ph d1 521^(C) 238 Me Me CH₂Ph OCH₂Ph d2 521^(C)

EXAMPLES 239-240

[1095] The compounds of Examples 239-240 were synthesized in a manneranalogous to procedures described for Example 199 using the appropriatestarting materials.

Exam- ple R′ R¹ R″ isomer MS 239 CF₃CH₂ CH₂-2-Pyr CH═CH-2,4-di-F—Ph d1622^(C) 240 CF₃CH₂ CH₂-2-Pyr CH═CH-4-Cl—Ph d1 620^(C)

EXAMPLES 241-251

[1096] The compounds of Examples 241-251 were synthesized in a manneranalogous to procedures described for Examples 2,197 and 198 using theappropriate starting materials.

Example R² R¹ R″ isomer MS 241 CF₃CH₂ CH₂-2,4-di-F—Ph OCH₂Ph d1,2612^(C) 242 CH₂Ph CH₂-2,4-di-F—Ph OCH₂Ph d1 620^(C) 243 CH₂PhCH₂-2,4-di-F—Ph OCH₂Ph d2 620^(C) 244 CF₃CH₂ CH₂Ph OCH₂Ph d1 576^(C) 245CF₃CH₂ CH₂Ph OCH₂Ph d2 576^(C) 246 CF₃CH₂ CH₂-2-Pyr OCH₂Ph d1 577^(C)247 CH₂Ph CH₂Ph OCH₂Ph d1 584^(C) 248 CH₂Ph CH₂Ph OCH₂Ph d2 584^(C) 249Me CH₂-2-Pyr OCH₂Ph d1,2 509^(C) 250 Et CH₂-2-Pyr OCH₂Ph d1,2 523^(C)251 Bn CH₂-2-Pyr OCH₂Ph d1,2 585^(C)

1. A compound of the formula

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, wherein HET is a heterocyclic moiety selected fromthe group consisting of

d is 0, 1 or 2; e is 1 or 2; A is a divalent radical, where the lefthand side of the radical as shown below is connected to C″ and the righthand side of the radical as shown below is connected to C′, selectedfrom the group consisting of —NR²—C(O)—NR²—, —NR²—S(O)₂—NR²—,—O—C(O)—NR²—, —NR²—C(O)—O—, —C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—,—NR²—C(O)—C(R⁹R¹⁰)—, —O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—,—C(O)—NR²—C(O)—, —C(R⁹R¹⁰)—C(O)—O—, —C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(O)—O—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—, —NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—,—C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—C(O)—NR², —C(R⁹R¹⁰)—NR²—C(O)—NR²—,—NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, —C(O)—N═C(R¹¹)—NR₂—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—, —C(R⁹R¹⁰)—NR —,—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—-C(R⁹R¹⁰)—, —C(R⁹R¹⁰)C(R⁹R¹⁰)—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalentbond or CH₂; W is CH or N; X is CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O orNR²; Z is C═O, C═S or S(O)₂; G¹ is hydrogen, halo, hydroxy, nitro,amino, cyano, phenyl, carboxyl, —CONH₂, —(C₁-C₄)alkyl optionallyindependently substituted with one or more phenyl, one or more halogensor one or more hydroxy groups, —(C₁-C₄)alkoxy optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, —(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl,N,N-di-(C₁-C₄)alkylamino, —(C₂-C₆)alkenyl optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, —(C₂-C₆)alkynyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, —(C₃-C₆)cycloalkyl optionally independently substituted with oneor more (C₁-C₄)alkyl groups, one or more halogens or one or more hydroxygroups, —(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G²and G³ are each independently selected from the group consisting ofhydrogen, halo, hydroxy, —(C₁-C₄)alkyl optionally independentlysubstituted with one to three halo groups and —(C₁-C₄)alkoxy optionallyindependently substituted with one to three halo groups; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N (X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), (CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡—C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—,—OC(O)N(X⁶)— or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said(CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹ areoptionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;R^(1A) is selected from the group consisting of hydrogen, F, Cl, Br, I,(C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyi(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″; R² is hydrogen,(C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹;where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2or 3 independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl-A¹,—(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,—(C₁-C₅)alkyl-X¹—(C₀-C₅)alkyl-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substitutents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷ as a ring member, X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and when R⁶ is a bond then L is N(X²) and each r inthe definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 2. Acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 1 wherein R⁴ ishydrogen or methyl; X⁴ is hydrogen; R⁶ is

where Z¹ is a bond and a is 0 or 1; X⁵ and X^(5a) are each independentlyselected from the group consisting of hydrogen, CF₃, phenyl andoptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with OX² or A¹; where A¹ in the definition of X⁵ and X^(5a)is imidazolyl, phenyl, indolyl, p-hydroxyphenyl, (C₅-C₇)cycloalkyl,—S(O)_(m)(C₁-C₆)alkyl, —N(X²)(X²) or —C(O)N(X²)(X²); R⁷is hydrogen or(C₁-C₃)alkyl; or X⁵ and R⁷ are taken together and form a (C₁-C₅)alkylenebridge; and R⁸ is hydrogen or (C₁-C₃)alkyl optionally substituted withone or two hydroxy groups.
 3. A compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 2 wherein b is 0; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,(C₁-C₃)alkyl and hydroxy(C₁-C₃)alkyl; and R³ is selected from the groupconsisting of thienyl-CH₂—O—CH₂—, pyridyl-CH₂—O—CH₂—,thiazolyl-CH₂—O—CH₂—, 1-indolyl-CH₂—, 2-indolyl-CH₂—, 3-indolyl-CH₂—,1-naphthyl-CH₂, 2-naphthyl-CH₂—, 1-benzimidazolyl-CH₂—,2-benzimidazolyl-CH₂—, phenyl-(C₁-C₄)alkyl, 2-pyridyl-(C₁-C₄)alkyl-,3-pyridyl-(C₁-C₄)alkyl-, 4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂—,thienyl-(C₁-C₄)alkyl-, phenyl-(C₀-C₃)alkyl-O—CH₂—,phenyl-CH₂-O-phenyl-CH₂—, phenyl-O—CH₂—CH₂— and 3benzothienyl-CH₂—;where the aryl portion(s) of the groups defined for R³ are eachoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 4. A compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 3 wherein R⁴ is hydrogen; a is 0;X⁵ and X^(5a) are each independently selected from the group consistingof hydrogen, methyl or hydroxymethyl, provided that when X⁵ is hydrogenthen X^(5a) is not hydrogen; R⁷ and R⁸ are each hydrogen; and R³ isselected from the group consisting of 3-indolyl-CH₂—, 1-naphthyl-CH₂—,2-naphthyl-CH₂—, phenyl-(C₁-C₄)alkyl-, 2-pyridyl-(C₁-C₄)alkyl-,3-pyridyl-(C₁-C₄)alkyl-, 4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂—,thienyl-(C₂-C₄)alkyl-, phenyl-(C₀-C₃)alkyl-O—CH₂—, 3-benzothienyl-CH₂—,thienyl-CH₂—O—CH₂—, thiazolyl-CH₂O—CH₂—, pyridyl-CH₂—O—CH₂— andphenyl-O—CH₂—CH₂—; where,the aryl portion(s) of the groups defined forR³ are each optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F. Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 5. A compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 4 wherein R¹ is (CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl; A¹ in the definition ofR¹ is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH3, OCF₂H, OCF₃ and CF₃; thecycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluoroatoms; q is 1 or 2;t is 1 or 2; R³ is phenyl-CH₂—O—CH₂—,phenyl-CH₂—S-CH₂—, pyridyl-CH₂—O—CH₂—, thienyl-CH—O—CH₂—,thiazolyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— or 3-indolyl-CH₂—; where the carbonatom bearing the substituent R³ is of the (R)-configuration; where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; andX⁵ and X^(5a) are each methyl.
 6. A compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 5 wherein HET is


7. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 6 wherein Z isS(O)₂; Q is a covalent bond; X is CH₂; and Y is CH₂ or NR²; R² ishydrogen, (C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where thealkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1, 2 or 3 fluoro groups.
 8. A compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 7 wherein Y is CH₂.
 9. A compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 8 wherein R¹ is —CH₂—A¹ where A¹ isphenyl, pyridyl or thiazolyl, optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and R³ isselected from the group consisting of 3-indolyl-CH₂₋, phenyl-(CH₂)₃—,phenyl-CH₂—O—CHr and thiazolyl-CH₂—O—CH₂—, where the aryl portion of thegroups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.
 10. A compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or a prodrug according to claim 9 wherethe compound is the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R)diastereomer or the 3a(S),1(R) diastereomer of2-amino-N-[2-(3a-benzyl-1,1-dioxo-hexahydro-1-thia-5,7a-diaza-inden-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.11. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 6 wherein Z isC═O; Q is a covalent bond; X is CH₂; and Y is NR²; R² is hydrogen,(C₁-C₅)alkyl or —(C₀-C₂)alkyl-(C₃₋C₈)cycloalkyl; where the alkyl andcycloalkyl groups in the definition of R² are optionally substitutedwith 1, 2 or 3 fluoro groups.
 12. A compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 11 wherein R¹ is —CH₂—A¹ where A¹ is phenyl,pyridyl or thiazolyl, optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; R² ishydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluoro groups;and R³ is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂-and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.
 13. A compound or a prodrug of such compound or apharmaceutically acceptable salt of the compound or prodrug according toclaim 12 where the compound is the 8a(R,S),1(R) diastereomeric mixture,the 8a(R),1(R) diastereomer or the 8a(S),1 (R) diastereomer of2-amino-N-[2-(8a-benzyl-2-methyl-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.
 14. A compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 6 wherein Z is C═O; Q is a covalentbond; X is CH₂; and Y is O.
 15. A compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 14 wherein R¹ is —CH₂—A¹ where A¹ is phenyl,pyridyl or thiazolyl, optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; and R³ isselected from the group consisting of 3-indolyl-CH₂—, phenyl-(CH₂)₃—,phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where the aryl portion ofthe groups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.
 16. A compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 15 wherethe compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R)diastereomer or the 8a(S), 1(R) diastereomer of the compound selectedfrom the group consisting of2-amino-N-[2-(8a-benzyl-3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-thiazol-4-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamideand2-amino-N-[1-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-3-ylmethyl-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide.17. A compound according to claim 6 wherein Z is C═O or S(O)₂; Q is acovalent bond; X is C═O; and Y is NR²; R² is hydrogen, (C₁-C₅)alkyl or—(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where the alkyl and cycloalkyl groupsin the definition of R² are optionally substituted with 1, 2 or 3 fluorogroups.
 18. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 17wherein Z is C═O; R¹ is —CH₂—A¹, where A¹ in the definition of R¹ isphenyl or pyridyl where said phenyl or pyridyl is optionally substitutedwith one to three substituents, each substituent being independentlyselected from the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ andCF₃; and R³ is phenyl-CH₂—O—CH₂—, pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)₃—,3-indolyl-CH₂— or thiazolyl-CH₂—O—CH₂—, where the aryl portion of thegroups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.
 19. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 18wherein R² is hydrogen or (C₁-C₃)alkyl where the alkyl group isoptionally substituted with 1-3 fluoro groups.
 20. A compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enanfiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 19 wherein R³ is phenyl-CH₂—O—CH₂—or phenyl-(CH₂)₃—, where the phenyl in the definition of R³ isoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 21. A compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 20 wherein R¹ is —CH₂—A¹ where A¹is phenyl, 2-pyridyl, 3-pyridyl, optionally substituted with 1-3 fluorogroups or 1-3 Chloro groups; R² is methyl or ethyl where the ethyl groupis optionally substituted with 1-3 fluoro groups; and R³ isphenyl-CH₂—O—CH₂—, where the phenyl is optionally substituted with 1-3fluoro groups, 1-3 Chloro groups or 1-2 CF₃ groups.
 22. A compound or aprodrug of such compound or a pharmaceutically acceptable sait of thecompound or prodrug according to claim 21 where the compound is the1(R),8a(R,S) diastereomeric mixture, the 1(R),8a(R) diastereomer or the1(R),8a(S) diastereomer of2-amino-N1-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-pyridin-3-ylmethyl-2-(2,2,2-trfluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide.23. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 21 wherein R¹ is—CH₂—A¹ where A¹ is phenyl optionally substituted with 1-2 chloro groupsor 1-2 fluoro groups; R² is methyl or —CH₂CF₃; and R³ isphenyl-CH₂—O—CH₂—, optionally substituted with 1-3 fluoro groups, 1-3chloro groups or 1-2 CF₃ groups.
 24. A compound or a prodrug of suchcompound or a pharmaceutically acceptable salt of the compound orprodrug according to claim 23 where the compound is selected from thegroup consisting of2-amino-N-[2-(8a-(R,S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo(1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R,S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamideand2-amino-N-{2-[8a-(R,S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.25. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-[2-(8a-(R)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.26. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-[2-(8a-(S)-benzyl-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5a]pyrazin-7-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,27. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(R)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.28. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-{1-(R)-benzyloxymethyl-2-[8a-(S)-(4-fluoro-benzyl)-2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.29. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-{2-[8a-(R)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.30. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 24 wherethe compound is2-amino-N-{2-[8a-(S)-benzyl-1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide.31. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 21 wherein R¹ is—CH₂—A¹ where A¹ is 2-pyridyl optionally substituted with 1-2 chlorogroups; R² is methyl or —CH₂CF₃; and R³ is phenyl-CH₂—O—CH₂—, optionallysubstituted with 1-3 fluoro groups, 1-3 chloro groups or 1-2 CF₃ groups.32. A compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 31 wherethe compound is 2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide,2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,2-amino-N-[2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamideor2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl}-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl)2-methyl-propionamide.
 33. The compound or a prodrug of such compound ora pharmaceutically acceptable salt of the compound or prodrug accordingto claim 32 where the compound is2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.34. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.35. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl}-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl)-2-methyl-propionamide.36. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-benzyloxymethyl-2-[1,3dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-tfifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.37. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.38. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-(2,4-difluoro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}2-methyl-propionamide.
 39. The compoundor a prodrug of such compound or a pharmaceutically acceptable salt ofthe compound or prodrug according to claim 32 where the compound is2-amino-N-[2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide.40. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-[2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-1-(R)-(2-trifluoromethyl-benzyloxymethyl)-ethyl]-2-methyl-propionamide.41. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.42. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 32 wherethe compound is2-amino-N-{1-(R)-(4-chloro-benzyloxymethyl)-2-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide.43. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 6 wherein Z isC═O; Q is a covalent bond; X is C═O; and Y is CH₂.
 44. XA compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 43 wherein R¹ is —CH₂—A¹ where A¹is phenyl, pyridyl or thiazolyl, optionally substituted with one tothree substituents, each substituent being independently selected fromthe group consisting of fluoro, chloro, methyl, OCH₃, OCF₂H, OCF₃ andCF₃; and R³ is selected from the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃.
 45. A compound or a prodrug of such compound or apharmaceutically acceptable salt of the compound or prodrug according toclaim 44 where the compound is the 1(R), 8a(R,S) diastereomeric mixture,the 1(R),8a(R) diastereomer or the 1(R),8a(S) diastereomer of2-amino-N-{1-benzyloxymethyl-2-[8a-(4-fluoro-benzyl)-6,8-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-2-oxo-ethyl}-2-methyl-propionamide.46. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 5 wherein HET is


47. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceuticaqlly acceptable salt of thecompound, mixture, isomer or prodrug according to claim 46 wherein W isN; d is 1; e is 0 or 1; R² is hydrogen, (C₁-C₅)alkyl or—(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where the alkyl and cycloalkyl groupsin the definition of R² are optionally substituted with 1, 2 or 3 fluorogroups; G¹ is hydrogen, halo, hydroxy, -(C₁-C₂)alkyl optionallyindependently substituted with one to three halo groups or-(C₁-C₂)alkoxy optionally independently substituted with one to threehalo groups; G² is hydrogen, halo, hydroxy, -(C₁-C₂)alkyl optionallyindependently substituted with one to three halo groups or-(C₁-C₂)alkoxy optionally independently substituted with one to threehalo groups; and G³ is hydrogen.
 48. A compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 47 wherein R² is hydrogen or (C₁-C₃)alkyloptionally substituted with 1-3 fluoro groups; R³ is selected from thegroup consisting of 3-indolyl-CH₂—, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂—and thiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups definedfor R³ is optionally substituted with one to three substituents, eachsubsttuent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃; and G¹, G² and G³are each independently hydrogen, Cl or F.
 49. A compound or a prodrug ofsuch compound or a pharmaceutically acceptable salt of the compound orprodrug according to claim 48 where the compound is2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-oxo-2-(9-oxo-1,2,4a,9-tetrahydro-4H-3,9a-diaza-fluoren-3-y)-ethyl]-2-methyl-propionamide.50. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 4 wherein HET is


51. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 50 wherein X⁵and X^(5a) are each methyl; d is 1; e is 1; R¹ is —(CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl; A¹ in the definition ofR¹ is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; thecycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluorogroups; t is 1 or 2; q is 1 or 2; and R² is hydrogen, (C₁-C₅)alkyl or-(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where the alkyl and cycloalkyl groupsin the definition of R² are optionally substituted with 1, 2 or 3 fluorogroups.
 52. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 51wherein R¹ is (C₁-C₆)alkyl optionally substituted with 1-3 fluorogroups; R² is hydrogen or (C₁-C₃)alkyl optionally substituted with 1-3fluoro groups; and R³ is selected from the group consisting of3-indolyl-CH₂—, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 53. A compound ora prodrug of such compound or a pharmaceutically acceptable salt of thecompound or prodrug according to claim 52 where the compound is2-amino-N-[2-(2,3-dimethyl-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-propionamide.54. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 5 wherein HET is


55. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 54 wherein A is—NR²—C(O)—O—; d is 1; e is 1; R¹ is —(CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl; A¹ in the definition ofR¹ is phenyl, pyridyl, thiazolyl or thien-yl, optionally substitutedwith one to three substituents, each substituent being independentlyselected from the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ andCF₃; the cycloalkyl and alkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3fluoro groups; t is 1 or 2; q is 1 or 2; R^(1A) is hydrogen or methyl;and R² is hydrogen, (C₁-C₅)alkyl, -(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl or(C₁-C₂)alkyl-A¹, where A¹ in the definition of R² is pyridyl; where thealkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1-3 fluoro groups.
 56. A compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 55 wherein R¹ is —CH₂—A¹ where A¹ is phenyl,pyridyl or thiazolyl, optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; R² ishydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluoro groups;R³ is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)3-, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and R^(1A) is hydrogen.
 57. A compound or a prodrug ofsuch compound or a pharmaceutically acceptable salt of the compound orprodrug according to claim 56 where the compound is the 3a(R,S)-7a(R,S)diastereomeric mixture, the 3a(R),7a(R) diastereomer, the 3a(S),7a(S)diastereomer, the 3a(R),7a(S) diastereomer or the 3a(S),7a(R)diastereomer of the compound selected from the group consisting of3a-7a-2-amino-N-[2-(3a-benzyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-(3-methyl-2-oxo-3a-pyridin-3-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,3a-7a-2-amino-N-[2-(3a-benzyl-3-methyl-2-oxo-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-propionamideand3a-7a-2-amino-N-[1-(R)-benzyloxymethyl-2-oxo-2-(2-oxo-3a-pyridin-2-ylmethyl-hexahydro-oxazolo[4,5-c]pyridin-5-yl)-ethyl]-2-methyl-propionamide.58. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 54 wherein A is—C(O)—NR²—CH₂—, —C(O)—O—CH₂—, —C(O)—NR²—C(O)—, —CH₂—NR¹²—CH₂— or—C(O)—NR²—CH₂—CH₂—; d is 1; e is 1; R¹ is —(CH₂)_(t)—A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl; A¹ in the definition ofR¹ is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; thecycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy or 1-3 fluorogroups; t is 1 or 2; q is 1 or 2; R^(1A) is hydrogen or methyl; and R²is hydrogen, (C₁-C₅)alkyl, —(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where thealkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1-3 fluoro groups.
 59. A compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 58 wherein R¹ is —CH₂—A¹ where A¹ is phenyl,pyridyl or thiazolyl, optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; R² ishydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluoro groups;and R³ is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and R^(1A) is hydrogen.
 60. A compound or a prodrug ofsuch compound or a pharmaceutically acceptable salt of the compound orprodrug according to claim 59 where the compound is selected from thegroup consisting of2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S), 1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S), 1(R) diastereomer of2-amino-N-[2-(3a-benzyl-3-oxo-hexahydro-furo[3,4-c]pyridin-5-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide,the 3a(R,S),1(R) diastereomeric mixture, the 3a(R),1(R) diastereomer orthe 3a(S), 1(R) diastereomer ofN-[2-(2-acetyl-3a-benzyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-(1H-indol-2-ylmethyl)-2-oxo-ethyl]-2-amino-2-methyl-propionamideand the 8a(R,S), 1(R) diastereomeric mixture, the 8a(R), 1(R)diastereomer or the 8a(S),1(R) diastereomer of2-amino-N-[2-(8a-benzyl-7-methyl-8-oxo-octahydro-[2,7]naphthyridin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide.61. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 54 wherein R¹ is—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl; A¹ in thedefinition of R¹ is phenyl, pyridyl, thiazolyl or thienyl, optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃; the cycloalkyl and alkyl groups in the definitionof R¹ are optionally substituted with (C₁-C₄)alkyl, hydroxy,(C₁-C₄)alkoxy, or 1-3 fluoro groups; t is 1 or 2; q is 1 or 2; R^(1A) ishydrogen or methyl; R² is hydrogen, (C₁-C₅)alkyl or-(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where the alkyl and cycloalkyl groupsin the definition of R² are optionally substituted with 1-3 fluorogroups; d is 1; e is 1; and R⁹ and R¹⁰ are each hydrogen.
 62. A compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 61 wherein R¹ is —CH₂—A¹ where A¹is phenyl, pyridyl or thiazolyl, optionally substituted with one tothree substituents, each substituent being independently selected fromthe group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; R² ishydrogen or (C₁-C₃)alkyl optionally substituted with 1-3 fluoro groups;and R³ is selected from the group consisting of 3-indolyl-CH₂-,phenyl-(CH₂)₃-, phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃,OCF₂H and CF₃; and R^(1A) is hydrogen.
 63. A compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 4 wherein HET is

Z is C═O or S(O)₂; Q is a covalent bond; X is C═O; Y is NR²; R² ishydrogen, (C₁-C₅)alkyl or -(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl; where thealkyl and cycloalkyl groups in the definition of R² are optionallysubstituted with 1, 2 or 3 fluoro groups; R¹ is hydrogen; and R³ isselected from the group consisting of phenyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, phenyl-(CH₂)₃—, 3-indolyl-CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting ofmethylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.
 64. A compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 63 wherein Z is C═O; R² is hydrogenor (C₁-C₃)alkyl optionally substituted with 1-3 fluoro groups.
 65. Acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enanfiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 64 wherein R³ isselected from the group consisting of 3-indolyl-CH₂—, phenyl-(CH₂)₃—,phenyl-CH₂—O—CH₂— and thiazolyl-CH₂—O—CH₂—, where the aryl portion ofthe groups defined for R³ is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of methylenedioxy, F, Cl, CH₃, OCH₃, OCF₃, OCF₂H andCF₃.
 66. A compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 65 wherethe compound is8a-(R,S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yI)-2-oxo-ethyl]-2-methyl-propionamide.67. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 66 wherethe compound is8a-(R)-2-amino-N-[1-(R)-(1H-indol-3ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.68. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 66 wherethe compound is8a-(S)-2-amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.69. A method for increasing levels of endogenous growth hormone in ahuman or other animal which comprises administering to such human oranimal an effective amount of a compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 70. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 71. Apharmaceutical composition useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprises a pharmaceutically acceptable carrier, an effective amount ofa compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 1 and a growthhormone secretagogue selected from the group consisting of GHRP-6,Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2and B-HT920 or an analog thereof.
 72. A method for treating orpreventing osteoporosis and/or frailty which comprises administering toa human or other animal in need of such treatment or prevention anamount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in treating or preventing osteoporosis and/orfrailty.
 73. A method for treating or preventing diseases or conditionswhich may be treated or prevented by growth hormone which comprisesadministering to a human or other animal in need of such treatment orprevention an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in promoting release of endogenous growth hormone.74. A method according to claim 73 wherein the disease or condition iscongestive heart failure, frailty associated with aging or obesity. 75.A method according to claim 74 wherein the disease or condition iscongestive heart failure.
 76. A method according to claim 74 wherein thedisease or condition is frailty associated with aging.
 77. A method foraccelerating bone fracture repair, attenuating protein catabolicresponse after a major operation, reducing cachexia and protein loss dueto chronic illness, accelerating wound healing, or accelerating therecovery of burn patients or patients having undergone major surgery,which method comprises administering to a mammal in need of suchtreatment an amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1which is effective in promoting release of endogenous growth hormone.78. A method according to claim 77 wherein the method is foraccelerating the recovery of patients having undergone major surgery.79. A method according to claim 77 wherein the method is foraccelerating bone fracture repair.
 80. A method for improving musclestrength, mobility, maintenance of skin thickness, metabolic homeostasisor renal homeostasis, which method comprises administering to a human orother animal in need of such treatment an amount of a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 1 which is effective in promotingrelease of endogenous growth hormone.
 81. A method for the treatment orprevention of osteoporosis and/or frailty which comprises administeringto a human or other animal with osteoporosis and/or frailty effectiveamounts of a bisphosphonate compound and a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 82. A method for the treatment ofosteoporosis and/or frailty according to claim 81 wherein thebisphosphonate compound is alendronate.
 83. A method for the treatmentof osteoporosis and/or frailty according to claim 81 wherein thebisphosphonate compound is ibandronate.
 84. A method for the treatmentor prevention of osteoporosis and/or frailty which comprisesadministering to a human or other animal with osteoporosis and/orfrailty effective amounts of estrogen or Premarin® and a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomericaklly enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 1 and, optionally, progesterone.85. A method for the treatment of osteoporosis and/or frailty whichcomprises administering to a human or other animal with osteoporosisand/or frailty effective amounts of calcitonin and a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enanfiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 86. A method to increase IGF-1levels in a human or other animal deficient in IGF-1 which comprisesadministering to a human or other animal with IGF-1 deficiency acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enanfiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 87. A methodfor the treatment of osteoporosis and/or frailty which comprisesadministering to a human or other animal with osteoporosis andlorfrailty effective amounts of an estrogen agonist or antagonist and acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 88. A methodaccording to claim 87 wherein the estrogen agonist or antagonist istamoxifen, droloxifene, raloxifene or idoxifene.
 89. A method accordingto claim 87 wherein the estrogen agonist or antagonist iscis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene2-ol;(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-6-phenyl-5[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or 1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6hydroxy-1,2,3,4-tetrahydro-isoquinoline.
 90. A method for enhancing growth andimproving carcass quality of an animal other than humans which comprisesadministering to said animal an effective amount of a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomercallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 91. A method for enhancing feedefficiency in an animal other than humans which comprises administeringto said animal an effective amount of a compound or a stereoisomercmixture thereof, diastereomercally enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 92. A method for increasing milkproduction in a female mammal which comprises administering to saidfemale mammal an effective amount of a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 93. A method for increasing piglet number,increasing pregnancy rate in sows, increasing viability of piglets,increasing weight of piglets or increasing muscle fiber size in pigletswhich comprises administering to a sow or piglet an effective amount ofa compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 94. A methodfor increasing muscle mass, which method comprises administering to ahuman or other animal in need of such treatment an amount of a compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a. prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 1 which is effective in promotingrelease of endogenous growth hormone.
 95. A method for promoting growthin growth hormone deficient children which comprises administering to agrowth hormone deficient child a compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 1 which is effective in promoting release ofendogenous growth hormone.
 96. A method for the treatment or preventionof congestive heart failure, obesity or frailty associated with aging,which comprises administering to a human or other animal in need thereofeffective amounts of a functional somatostatin antagonist and a compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 97. A method according to claim96 wherein the functional somatostatin antagonist is an alpha-2adrenergic agonist and the other animal is a dog, cat or a horse.
 98. Amethod according to claim 97 wherein the alpha-2 adrenergic agonist isclonidine, xylazine or medetomidine.
 99. A method for treating insulinresistance in a mammal, which comprises administering to said mammal aneffective amount of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1.100. A method for increasing the endogenous production or release ofgrowth hormone in a human or other animal which comprises administeringeffective amounts of a compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 1and a growth hormone secretagogue selected from the group consisting ofGHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1,IGF-2 and B-HT920 or an analog thereof.
 101. A pharmaceuticalcomposition useful for treating or preventing osteoporosis and/orfrailty which comprises a pharmaceutically acceptable carrier, an amountof a bisphosphonate compound and an amount of a compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 102. A pharmaceuticalcomposition useful for treating or preventing osteoporosis and/orfrailty which comprises a pharmaceutically acceptable carrier, an amountof estrogen or Premarine, an amount of a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 1 and, optionally, an amount of progesterone.103. A pharmaceutical composition useful for treating osteoporosisand/or frailty which comprises a pharmaceutically acceptable carrier, anamount of calcitonin and an amount of a compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim
 1. 104. A pharmaceutical composition usefulfor treating preventing congestive heart failure, obesity or frailtyassociated with aging, which comprises a pharmaceutically acceptablecarrier, an amount of an alpha-2 adrenergic agonist and an amount of acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim
 1. 105. Apharmaceutical composition according to claim 104 wherein the alpha-2adrentergic agonist is clonidine, xylazine or medetomidine.
 106. Amethod for increasing levels of endogenous growth hormone, whichcomprises administering to a human or other animal in need thereofeffective amounts of a functional somatostatin antagonist and a compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomercallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim
 1. 107. A method according to claim99 wherein the condition associated with insulin resistance is type Idiabetes, type II diabetes, hyperglycemia, impaired glucose tolerance oran insulin resistant syndrome.
 108. A method according to claim 99wherein the condition associated with insulin resistance is associatedwith obesity or old age.
 109. A compound or a stereoisomeric mixturethereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 6 wherein Z is C═O; Q is a covalent bond; Yis CR⁹R¹⁰ where R⁹ in the definition of Y is selected from the groupconsisting of hydrogen, fluoro, hydroxy and (C₁-C₂)alkyl optionallysubstituted with 1-3 fluoro groups; and R¹⁰ in the definition of Y isselected from the group consisting of hydrogen, fluoro, and (C₁-C₂)alkyloptionally substituted with 1-3 fluoro groups with the proviso that R¹⁰cannot be fluoro when R⁹ is hydroxy; and X is CHR⁹ where R⁹ in thedefinition of X is selected from the group consisting of hydrogen,fluoro, hydroxy and (C₁-C₂)alkyl optionally substituted with 1-3 fluorogroups.
 110. A compound or a stereoisomeric mixture thereof,diastereomerically enriched, diastereomerically pure, enantiomericallyenriched or enantiomerically pure isomer thereof, or a prodrug of suchcompound, mixture or isomer thereof, or a pharmaceutically acceptablesalt of the compound, mixture, isomer or prodrug according to claim 109wherein R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and R³ is selected form the group consistingof 3-indolyl-CH₂—, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃.
 111. A compound or a stereoisomericmixture thereof, diastereomerically enriched, diastereomerically pure,enantiomerically enriched or enantiomerically pure isomer thereof, or aprodrug of such compound, mixture or isomer thereof, or apharmaceutically acceptable salt of the compound, mixture, isomer orprodrug according to claim 110 wherein X is CH₂; Y is CR⁹R¹⁰ where R⁹and R¹⁰ in the definition of Y are independently selected from the groupconsisting of hydrogen, fluoro, and (C₁-C₂)alkyl optionally substitutedwith 1-3 fluoro groups.
 112. A compound or a prodrug of such compound ora pharmaceutically acceptable salt of the compound or a prodrugaccording to claim 111 where the compound is the 8a(R,S),1(R)diastereomeric mixture, the 8a(R),1(R) diastereomer or the 8a(S), 1(R)diastereomer of2-amino-N-[2-(8a-benzyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-1-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamideor 2-amino-N-[1-benzyloxymethyl-2-oxo-2-(6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-ethyl]-2-methyl-propionamide.113. A compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or a prodrug according to claim 12 wherethe compound is the 8a(R,S),1(R) diastereomeric mixture, the 8a(R),1(R)diastereomer or the 8a(S), 1(R) diastereomer of 2-amino-N-{1-benzyloxymethyl-2-oxo-2-[3-oxo-8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-ethyl}2-methyl-propionamide;2-amino-N-{1-benzyloxymethyl-2-[8a-(2,4-difluoro-benzyl)-3-oxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethy}2-methyl-propionamide;2-amino-N-[l-benzyloxymethyl-2-oxo-2-(3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-ethyl]-2-methyl-propionamide; or2-amino-N-[1-benzyloxymethyl-2-(2-ethyl-3-oxo-8a-pyridin-2-ylmethyl-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl]-2-methyl-propionamide.
 114. A compoundor a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 20 wherein R¹ is —CH₂—A¹ where A¹is phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted with 1-3 F,1-3 Cl; R² is methyl or ethyl where the ethyl group is optionallysubstituted with 1-3 F; and R³ is phenyl-(CH₂)₃—, where the phenyl isoptionally substituted with 1-3 F, 1-3 Cl or 1-2 CF₃;
 115. A compound ora stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 114 wherein R¹ is —(CH₂)—A¹ whereA¹ is 2-pyridyl, optionally substituted with 1-2 Cl; and R² is methyl or—CH₂CF₃.
 116. A compound or a prodrug of such compound or apharmaceutically acceptable salt of the compound or a prodrug accordingto claim 115 where the compound is 2-amino-N{1 -(R)-[1,3-dioxo-8a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}2-methyl-propionamide.117. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or a prodrug according to claim 116where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4-phenyl-butyl)}-2-methyl-propionamide.118. The compound or a prodrug of such compound or a pharmaceuticallyacceptable salt of the compound or a prodrug according to claim 116where the compound is2-amino-N-{1-(R)-[1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carbonyl]-(4phenyl-butyl)}-2-methyl-propionamide.119. A compound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enanfiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 58 wherein A is—C(O)—NR²—CH₂—; R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; R² is hydrogen or —(C₁-C₃)alkyl or—(C₀-C₂)alkyl-(C₃-C₅)cycloalkyl where the alkyl and cycloalkyl groups inthe definition of R² are optionally substituted with 1-3 fluoro groups;R³ is selected form the group consisting of 3-indolyl-CH₂—,phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂ and thiazolyl-CH₂—O—CH₂—, where thearyl portion of the groups defined for R³ is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; andR^(1A) is hydrogen.
 120. A compound or a prodrug of such compound or apharmaceutically acceptable salt of the compound or a prodrug accordingto claim 119 where the compound is the 3a(R,S),7a(R,S) diastereomericmixture, the 3a(R),7a(R) diastereomer, the 3a(S),7a(S) diastereomer, the3a(R),7a(S) diastereomer, or the 3a(S),7a(R) diastereomer of2-amino-N-[2-(3a-benzyl-2-cyclopropyl-3-oxo-octahydro-pyrrolo[3,4c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;2-amino-N-[2-(3a-benzyl-2-methyl-3-oxo-octahydro-pyrrolo[3,4c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-2-methyl-propionamide;or 2-amino-N-[1(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-pyridin-2-ylmethyl-octahydro-pyrrolo[3,4-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide.121. A compound of the formula

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, wherein HET is a heterocyclic moiety selected fromthe group consisting of

d is 0, 1 or 2; e is I or 2; A is a divalent radical, where the lefthand side of the radical as shown below is connected to C″ and the righthand side of the radical as shown below is connected to C′, selectedfrom the group consisting of —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,'C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—C(O)—NR²—,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—NR²—C(R⁹R¹⁰)—, —NR²—C(R⁹R¹⁰)—, —NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—, —C(R⁹R¹⁰)—NR¹²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—, —C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—, —O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—O—,—C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—, —C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and—C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalent bond or CH₂; W is CH or N; Xis R^(9a)R^(10a), C═CH₂ or C═O; Y is R⁹R¹⁰, O or NR²; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X)C(O)X⁶, —(CH₂)_(q)N(X)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, -(CH₂)_(q)N(X)S(O)2X⁶,-(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹—(CH₂)_(q)N(X⁶)C(O)N(X)(X⁸),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, 13(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N((NX(⁶)CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,(CH₂)_(q)S(O),(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹(CH₂)_(t)—A¹ or —(CH₂)_(q)-Y¹-(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C—C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,—(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶ ₁—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl-A¹,—(C₀-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl,—(C₁-C₅)alkyl-X¹—(C₀—C₅)alkyl-A¹ and—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C═C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X⁵a is optionally substitutedwith a substituent selected from the group consisting of A¹, OX²,—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with Xsa and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5-or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O—(C₁-C₆)alkyl, —S(O),(C₁-C₈)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹, R^(9a), R¹⁰ and R^(10a) are each independently hydrogen, fluoro,hydroxy, (C₁-C₄)alkoxy or (C₁- C₅)alkyl optionally substituted with 1 to5 halogroups, provided that at least one of R⁹, R^(9a), R¹⁰ or R^(10a)is present and is (C₁- C₄)alkoxy; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substitutents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷ as a ring member, X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and when R⁶ is a bond then L is N(X²) and each r inthe definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 122. Acompound or a stereoisomeric mixture thereof, diastereomericallyenriched, diastereomerically pure, enantiomerically enriched orenantiomerically pure isomer thereof, or a prodrug of such compound,mixture or isomer thereof, or a pharmaceutically acceptable salt of thecompound, mixture, isomer or prodrug according to claim 121 wherein HETis

R¹ is —(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;where A¹ in the definition or R¹ is phenyl, pyridyl, thiazolyl orthienyl, optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃; the cycloalkyl and alkyl groups inthe definition of R¹ are optionally substituted with (C₁-C₄)alkyl,hydroxy, (C₁-C₄)alkoxy or 1 to 3 fluoro atoms; q is 1 or 2; t is 1 or 2;R³ is selected form the group consisting of phenyl-CH₂—O—CH₂—,phenyl-CH₂—S—CH₂—, pyridyl-CH₂—O—CH₂—, thienyl-CH₂—O—CH₂—,3-indolyl-CH₂—, phenyl-(CH₂)₃— and thiazolyl-CH₂—O—CH₂—; where thecarbon atom bearing the substituent R³ is of the (R)-configuration;where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, CH₃, OCH₃,OCF₂H, OCF₃ and CF₃ R⁴ is hydrogen; R⁶ is

where Z¹ is a bond; X⁵ and X^(5a) are each methyl; a and b are each 0;R⁷ and R⁸ or each hydrogen; X⁴ is hydrogen.
 123. A compound or astereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug according to claim 122 wherein Z is C═O; Q is acovalent bond; Y is CR⁹R¹⁰ where R⁹ in the definition of Y is selectedfrom the group consisting of hydrogen, fluoro, hydroxy, (C₁-C₂)alkoxyand (C₁-C₂)alkyl optionally substituted with 1-3 fluoro groups; and R¹⁰in the definition of Y is selected from the group consisting ofhydrogen, fluoro, and (C₁-C₂)alkyl optionally substituted with 1-3fluoro groups with the proviso that R¹⁰ cannot be fluoro when R⁹ ishydroxy or (C₁-C₂)alkoxy; and X is CHR^(9a) where R⁹ in the definitionof X is selected from the group consisting of hydrogen, fluoro, hydroxy,(C₁-C₂)alkoxy and (C₁-C₂)alkyl optionally substituted with 1-3 fluorogroups, R¹ is —CH₂—A¹ where A¹ is phenyl, pyridyl or thiazolyl,optionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, CH₃,OCH₃, OCF₂H, OCF₃ and CF₃; and R³ is selected form the group consistingof 3-indolyl-CH₂-, phenyl-(CH₂)₃—, phenyl-CH₂—O—CH₂— andthiazolyl-CH₂—O—CH₂—, where the aryl portion of the groups defined forR³ is optionally substituted with one to three substituents, eachsubstituent being independently selectbd from the group consisting of F,Cl, CH₃, OCH₃, OCF₂H, OCF₃ and CF₃.
 124. A compound or a prodrug of suchcompound or a pharmaceutically acceptable salt of the compound or aprodrug according to claim 123 where the compound is the 8(R,S),8a(R,S)diastereomeric mixture, the 8(R),8a(R) diastereomer, the 8(S),8a(S)diastereomer, the 8(R),8a(S) diastereomer, or the 8(S),8a(R)diastereomer of 2-amino-N-[1(R)-benzyloxymethyl-2-(8-methoxy-6-oxo-8a-pyridin-2-ylmethyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-2-oxo-ethyl]-2-methyl-propionamide.
 125. A method ofclaim 73 wherein said condition is a sleep disorder.
 126. The L-tartratesalt of the compound of claim
 36. 127. A compound of the formula

where R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,-(CH₂)_(q)Ne(⁶)C(O)(CH₂)_(r)A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹—(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X)(CH₂)_(t)—A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(C H₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC₂)_(q)OC(O)N(X⁶)() ) —(CH₂)_(q)C(O)X⁶,—(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₁-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C—C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; m for each occurrence is 0, 1 or 2; q is 0, 1, 2, 3 or4; tis 0, 1, 2 or3; said (CH₂)_(q) group and (CH₂)t group in the definitionof R¹ are optionally independently substituted with hydroxy,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkylgroups; A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5 or6-membered ring, optionally having I to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; A¹for each occurrence is independently optionally substituted, on one oroptionally both rings if A¹ is a bicyclic ring system, with up to threesubstituents, each substituent independently selected from the groupconsisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, OX⁶,—C(O)N(X⁶((X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy,halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —S(O)₂N(X⁶)(X⁶),—N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹ ¹)02, -S(O)₂NX¹ ¹X¹²,—NX⁶S(O)₂X¹² ₁—NX⁶CONX¹¹X₁₂NX⁶S(O)₂NX⁶X₁—NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy; where X¹¹ is hydrogen or optionally substituted(C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, I to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to 3(C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl,imidazolyl, furyl or thienyl, provided that when X¹² is not hydrogen,the X¹² group is optionally substituted with one to three substituentsindependently selected from the group consisting of Cl, F, CH₃, OCH₃,OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂),; L¹ is C(X²)(X²), O., S(O)_(m) or N(X²); X⁶for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; and R² is hydrogen, (C₁-C₈)alkyl,-(C₁-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, -C(O)OX⁶, —C(O)N(X⁶)o(⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X), CF3, CN or 1, 2 or 3independently selected halo groups.
 128. A compound of claim 127 whereinR¹ is CH₂—A¹ and R² is CF₃CH₂—.
 129. A compound of claim 128 wherein A¹is 2-pyridyl.
 130. The compound of claim 129 which is8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazol1,5-a]pyrazine-1,3-dione.131. The L-tartrate salt of the compund of claim
 130. 132. A process forpreparing1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester comprising reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo([1,5-a]pyrazine-1,3dionewith D-tartaric acid in a reaction inert solvent at 0° C. to about roomtemperature for about 5 minutes to about 48 hours.
 133. A process forpreparing2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyddin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride comprising (a) reacting8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dionewith D-tartaric acid in a reaction inert solvent to form1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester; (b) reacting said1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylicacid tert-butyl ester with3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid in the presence of a tertiary amine and 1-propanephosphonic acidcyclic anhydride in a reaction inert solvent to form (1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acidtert-butyl ester; and (c) reacting said(1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acidtert-butyl ester with concentrated hydrochloric acid in a reaction inertsolvent to form 2-amino-N-(1 (R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propionamidehydrochloride.